Next Article in Journal
Special Issue: Resistance to Targeted Therapies in Human Cancer
Previous Article in Journal
A New Insight into MYC Action: Control of RNA Polymerase II Methylation and Transcription Termination
Previous Article in Special Issue
Antibacterial Effect of Silver Nanoparticles Is Stronger If the Production Host and the Targeted Pathogen Are Closely Related
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Biomedicines
Volume 11
Issue 2
10.3390/biomedicines11020413
biomedicines-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Nanotechnology as a Promising Approach to Combat Multidrug Resistant Bacteria: A Comprehensive Review and Future Perspectives

by
Helal F. Hetta
1,*,
Yasmin N. Ramadan
2,
Alhanouf I. Al-Harbi
3,
Esraa A. Ahmed
4,
Basem Battah
5,
Noura H. Abd Ellah
6,7,
Stefania Zanetti
8 and
Matthew Gavino Donadu
8,9,*
1
Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
2
Department of Microbiology and Immunology, Faculty of Pharmacy, Assiut University, Assiut 71515, Egypt
3
Department of Medical Laboratory, College of Applied Medical Sciences, Taibah University, Yanbu 46411, Saudi Arabia
4
Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
5
Department of Biochemistry and Microbiology, Faculty of Pharmacy, Syrian Private University (SPU), Daraa International Highway, 36822 Damascus, Syria
6
Department of Pharmaceutics, Faculty of Pharmacy, Assiut University, Assiut 71515, Egypt
7
Department of Pharmaceutics, Faculty of Pharmacy, Badr University in Assiut, Naser City, Assiut 2014101, Egypt
8
Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy
9
Hospital Pharmacy, Azienda Ospedaliero Universitaria di Sassari, 07100 Sassari, Italy
*
Authors to whom correspondence should be addressed.
Biomedicines 2023, 11(2), 413; https://doi.org/10.3390/biomedicines11020413
Submission received: 27 December 2022 / Revised: 20 January 2023 / Accepted: 26 January 2023 / Published: 31 January 2023
(This article belongs to the Special Issue Advances and New Perspectives in Pharmaceutical Microbiology)
Browse Figures
Review Reports Versions Notes

Abstract

:
The wide spread of antibiotic resistance has been alarming in recent years and poses a serious global hazard to public health as it leads to millions of deaths all over the world. The wide spread of resistance and sharing resistance genes between different types of bacteria led to emergence of multidrug resistant (MDR) microorganisms. This problem is exacerbated when microorganisms create biofilms, which can boost bacterial resistance by up to 1000-fold and increase the emergence of MDR infections. The absence of novel and potent antimicrobial compounds is linked to the rise of multidrug resistance. This has sparked international efforts to develop new and improved antimicrobial agents as well as innovative and efficient techniques for antibiotic administration and targeting. There is an evolution in nanotechnology in recent years in treatment and prevention of the biofilm formation and MDR infection. The development of nanomaterial-based therapeutics, which could overcome current pathways linked to acquired drug resistance, is a hopeful strategy for treating difficult-to-treat bacterial infections. Additionally, nanoparticles’ distinct size and physical characteristics enable them to target biofilms and treat resistant pathogens. This review highlights the current advances in nanotechnology to combat MDR and biofilm infection. In addition, it provides insight on development and mechanisms of antibiotic resistance, spread of MDR and XDR infection, and development of nanoparticles and mechanisms of their antibacterial activity. Moreover, this review considers the difference between free antibiotics and nanoantibiotics, and the synergistic effect of nanoantibiotics to combat planktonic bacteria, intracellular bacteria and biofilm. Finally, we will discuss the strength and limitations of the application of nanotechnology against bacterial infection and future perspectives.

1. Introduction

Antimicrobial resistance poses a serious threat to global public health, causing at least 1.27 million deaths globally and approximately 5 million fatalities in 2019. Each year, more than 2.8 million illnesses in the US are resistant to antibiotics. More than 35,000 people die as a result, according to CDC’s 2019 Antibiotic Resistance (AR) Threats Report [1].
Antimicrobial resistance may have an impact on individuals at every stage of life, as well as on the medical, veterinary, and agricultural sectors [2,3,4,5,6,7]. This makes it one of the most important public health issues in the entire world [1].
Rapid development of Ab resistance in microorganisms is directly related to overconsumption of Abs, their broad utilization in agriculture and the non-availability of novel antibiotics [8,9]. Due to the fact that repeated drug administration and greater doses are common nowadays, Antibiotic resistance has emerged against various types of antibiotics commonly used against harmful bacteria [10]. Development of Antibiotic resistance has a severe impact on the efficacy of antimicrobial medication and is linked to high fatality rates and high medical costs [11].
To be hazardous, bacteria do not necessarily need to be resistant to all antibiotics. Serious issues can result from resistance to even a single antibiotic. For example, second- and third-line treatments for antibiotic-resistant infections can harm patients by resulting in severe adverse effects, such as organ failure, and delaying treatment and recovery for weeks or even months. If antibiotics and antifungals become ineffective, we will be unable to treat infections and manage these public health problems [1,12,13,14,15,16].
To overcome this serious problem, nanotechnology and nanoparticles were developed in recent years to reduce and combat bacterial resistance, multidrug resistance (MDR) and even bacterial biofilm. Nanoparticles are engineered structures with sizes ranging from 1 to 100 nm (nm) [17]. Nanomaterials are used in a variety of medical applications, ranging from medical equipment to therapeutic agents, drug delivery systems, and diagnostic imaging systems [17].
Nanotechnology-based delivery systems are increasingly being evaluated as viable options for improving therapeutic efficacy by limiting drug degradation, increasing accumulation at infection sites, and reducing toxicity [18,19,20,21]. The NPs provide the most effective method of addressing MDR bacteria since they not only act as transporters for natural antibiotics and antimicrobials, but also actively combat bacteria. Moreover, loaded NPs have the capacity to safely and effectively transport a wide variety of treatments to the site of infection when they are bonded to their surface or enclosed within a structure [11,22,23,24,25].
Nanoparticles can act as inherent therapies (e.g., titanium dioxide (TiO2), zinc oxide (Zn O) NPs [26], copper (Cu) NPs [27], nickel (Ni) NPs) [28], selenium (Se) NPs [28,29,30], silver (Ag) NPs) [31,32] or as nano-carriers for antimicrobial agents “Nanobiotics” (e.g., liposomes, polymeric NPs, and dendrimers) [33,34].
Due to the ability of the NPs to carry medications to the target location in the ideal dosage range, protect them against deactivation, and boost their therapeutic effectiveness with fewer adverse effects, nanoparticles are considered a targeted therapy approach [22,24,35,36,37,38,39,40,41,42].
The nano-formulations’ small size, large surface area, and highly reactive nature allow them to penetrate biological barriers such as biofilm and have a high selectivity for bacterial cells [23,43,44]. The increased surface area of NPs makes it easier to load medications while the NPs sizes are tiny enough to penetrate biofilms and microbial cell walls. Additionally, NPs are quickly excreted through the kidney and have extended plasma half-lives [43,45].
Typically, the synthesis procedures and formulation conditions of nanoparticles, such as the type of reducing agent, temperature, concentration, and solvent, typically determine their antibacterial or biological properties [46,47].The behavior and activity of nanoparticle are significantly determined by chemical composition, shape, size and size distribution [48]. The antimicrobial properties of nanoparticles are also influenced by a number of factors, including temperature, pH, metal ion concentration, cell age, and reaction time [49].
Organic nanoparticles (e.g., liposomes, polymeric nanoparticles, micelles, ferritin) and inorganic nanoparticles (e.g., metal nanoparticles) have both been used to treat a variety of medical diseases [50]. Drug transport efficiency, bioavailability, and antibacterial activity have all been improved with the use of organic nanoparticles [51]. They have showed promise against viral infections, such as severe acute respiratory syndrome 2 (SARS-CoV-2) and have also been used to treat fungal infection [52,53,54,55,56].
The present variety of nanoparticulate antibacterial systems consists of liposomes, micelles, solid lipid nanoparticles, carriers nanogels, nanocapsules, nanotubes, dendrimers, emulsions, nanostructured lipid, quantum dots and polymeric NPs. They are slow-release nanoscale drug delivery systems that deliver drugs to targeted cells [54,57].
The most promising ones seem to be the metallic NPs. Several multi-drug resistant microorganisms are responsive to a variety of their activities [53,58]. Among all the nanoparticles, AgNps is the most studied and utilized [59].It is crucial to characterize metal NPs to understand their toxicity and mode of action. A variety of methods including UV–visible spectroscopy, single-particle inductively coupled plasma mass spectrometry, X-ray diffraction analysis, transmission electron microscopy (TEM), atomic force microscopy, Zeta potential measurement, dynamic light scattering and Fourier transform infrared spectroscopy analysis can be used for this purpose [60,61].
In this review, we will discuss the ways in which the bacteria develop resistance to conventional antibiotics, serious widespread of MDR and XDR bacteria. Moreover, we will discuss NPs as a trend approach to combat MDR organisms, their types and formulation and expected mechanism of action. Additionally, we will explain synergetic effect of NPs loaded with conventional antibiotics and the way this affects targeting of antibiotic and potentiate bacterial cell lysis as shown in Figure 1.

2. Development of Antibiotic Resistance

Bacteria are living entities that change over time. Their major goal is to multiply, endure, and spread as quickly as they can. Microbes, as a result, adapt to their environment and develop in ways that ensure their survival [62,63]. If anything, such as an antibiotic, inhibits their ability to develop, genetic changes may occur, rendering the bacteria resistant to the medicine and enabling them to survive [64].
Antibiotics can be rendered inactive by bacteria via a variety of molecular mechanisms [65] (Figure 2).
1.
Production of inactivating enzymes: The bacterium produces particular enzymes that precisely inactivate the antibiotic, causing it to lose its biological function. For instance, when β-lactam drugs are digested by β-lactamases, this occurs. Extended-spectrum β-lactamases (ESBLs), which have the same inactivating activity, are produced by some bacteria, making them challenging to eradicate. The enzymes acetyltransferase, phosphotransferase, and adenyl transferase are additional ones that can render certain antibiotics inactive [66,67,68,69].
2.
Changes and alterations in the antibiotic target: In the case of erythromycin resistance, for instance, methylation of an adenine residue in the peptidyl-transferase of r-RNA 23S reduces the enzyme’s affinity for the antibiotic without impairing protein synthesis. The alteration of penicillin-binding proteins (PBPs) by MRSA is another significant instance [70].
3.
Decrease in antibiotic uptake: Changes in the structural architecture of the cell’s surface casings can reduce the entry of an antibiotic. For example, a change or reduction in the quantity of porins or porin gene mutation may be the cause of the resistance in Gram-negative bacteria [71,72,73].
4.
Extrusion of drug outside the cell: Energy-driven drug efflux systems eliminate antibiotics that have been taken up by bacterium cells. Many times, bacterial cells that are resistant to antibiotics have upregulated efflux pumps [71,73,74,75,76].
5.
Activation of alternative metabolic pathways: The sulfonamides case serves as an explanation. In fact, bacteria exposed to sulfonamides are still able to produce folic acid through a different metabolic pathway [77].
6.
Transferring of resistance genes: As a result of bacterial communication and genetic information sharing, resistance genes propagate among bacterial populations [8,78].
7.
Inactive metabolic state of microorganism: The metabolically inert bacterial subpopulations known as persister cells have a lower antibacterial susceptibility than active ones [79].
8.
Extracellular polymeric substances (biofilm) formation: Due to electrostatic repulsion, some antibiotics, such aminoglycosides, are unable to penetrate the protective extracellular polymeric components of bacterial biofilms [78,80,81].

3. Spread of MDR and XDR Bacteria

Once a species gains resistance to an antibiotic, it eventually overcomes the combined drug effects, leading to development of multidrug-resistant (MDR) organisms which are resistant to antimicrobial drugs or combination treatments. By encouraging bacterial growth that was not immediately eliminated, this scenario occasionally encourages the spread of resistance [82,83,84,85].
Increased antibiotic resistance is among the world’s top three public health issues of the 21st century, according to the World Health Organization (WHO). The much more harmful bacteria, collectively known as ESKAPE (Enterococcus, Staphylococcus, Klebsiella, Actinobacter, Pseudomonas, and Enterobacter), are those that cause the most concern. They are all are connected to a high death rate [72,86,87,88]. The spread of MDR and extensively drug-resistant (XDR) bacteria continues to represent a severe threat to human and animal health due to their high mortality, morbidity, and prices of medication to combat them [89,90,91,92]. This is made worse by a number of bacterial strains’ capacity to form biofilms, which is linked to 65–80% of human illnesses [93]. Antibiotic susceptibility of biofilm cells is typically 100–1000 times lower than that of planktonic cells [94]. Drug resistance in biofilms is caused by various factors, including decreased drug absorption throughout the extracellular polymeric matrix, decreased intracellular drug level, decreased bacterial metabolism, and transferring resistant genes [95,96]. MDR causes blockage in the fight against disease and decreases treatment effectiveness, which causes the patient’s infection to last longer than expected. Immunocompromised patients such as those with chronic diseases, receiving cancer chemotherapy, immunosuppressive drugs or undergo organ transplantation are more vulnerable to MDR infection. Additionally, the treatment cost has also increased as a result of MDR since microorganisms have developed resistant to commercially accessible Abs, necessitating the adoption of a more expensive one [97] (Figure 3). The potential for MDR to spread over the world is boosted by the expansion of international trade and travel.
According to reports, multidrug-resistant bacteria are responsible for at least 700,000 deaths annually across the globe, including 23,000 deaths in the US and 25,000 deaths in the EU [98]. According to reports from the WHO, misuse and overuse of antibiotics account for approximately 80% of MDR or XDR bacteria, and these infections are linked to serious negative effects [87]. It is also predicted that if no action is taken to combat bacterial resistance or create new medicines, 10 million individuals will die globally from bacterial diseases by the year 2050 [99]. As MDR pathogens and other resistant organisms proliferate, there are currently few therapeutic and preventative options available [87]. The lack of success with conventional antibiotics forces the quest for more effective treatments. Most bacterial infections can be successfully treated using nanoparticles, particularly those caused by MDR pathogens. Antibiotics and nanoparticles can be employed separately or in combination to produce strong synergistic effects [54].

4. Types and Formulations of Nanoparticles

4.1. Organic NPs

Organic NPs have been extensively studied over the recent years and contain a variety of types. The first nano-scale medication licensed for medical use is called a liposome [100]. Liposomes are biocompatible, biodegradable, and nontoxic vesicles. They consist of one or more outer lipid layers and core holding hydrophilic or hydrophobic medication [101,102].
Liposomal Np core has high drug loading capacity, and so, by encapsulating hydrophilic antimicrobial drugs in liposomal NP core, it is possible to protect them from degradation in vivo. Bassetti M et al. studied the effect of aerosolized liposomal antimicrobials (ciprofloxacin, tobramycin, amphotericin B and amikacin) and their curative significant effect to prevent and treat acute and chronic respiratory tract infection [103].
Another type of organic NPs is polymer-based, which has unique structural arrangements for drug delivery created by numerous monomers [104,105]. Polymeric NPs include polylactic-co-glycolic acid (PLGA), which is formed through co-polymerization of lactic and glycolic acid [106,107]; dendrimers, which are characterized with a 3D branching architecture [108]; and micelles, which are distinguished by polymer self-assembly into nano-aggregates [109].

4.2. Inorganic NPs

Inorganic NPs may be categorized into metal nanoparticles and nanoparticles made of metal oxide. They are characterized with their own antibacterial activities. Due to their unique antibacterial activities, they may be used alone or loaded with antibiotic and exert dual mechanisms (Figure 4) [110].
Metal NPs my include Ag [110,111], Au [112,113], Cu [27,110], Si [114], Ni [28], and Se [28,30], and metal oxide may include ZnO [26,115,116], TiO2 [117,118,119], CuO [120], MgO [116] and SiO2 [121].
Organic NPs have advantage over inorganic type as they have higher surface area to volume ratio. Unfortunately, they have poorer biodegradability and biocompatibility [122].
Inorganic NPs may have some sort of cytotoxicity and this effect depends on their size and charge. This cytotoxicity is dose-related [123].
Carbon nanotubes are tubes made of carbon with diameters typically measured in nanometers, characterized by a vast promise in the drug delivery area due to its distinct biological, physical, and chemical properties [124,125].
Mesoporous nanoparticle carriers, which are subtypes from silica NPs, have high surface area, strong framework, and are porous. This porous nature creates high content of internal pores and so is loaded with maximum number of antimicrobials [126,127,128].

4.3. Hybrid NPs

Hybrid NPs are formed from combination of organic and inorganic NPs in a single composite drug delivery system. Therefore, this composite system improves biological features and increases treatment efficacy and decreases toxicity and resistance [129].
Lipid polymer hybrid NPs are constructed from polymeric core and outer lipid sheath. It has been established and proved that these hybrid NPs are an effective drug delivery system [130]. These hybrid NPs combine the advantages of both lipids and polymers; therefore, they are characterized with biocompatibility, structural rigidity, and sustained drug release. This type can also be loaded with both hydrophilic and hydrophobic drugs and achieve perfect drug targeting and release [131,132].
In recent study, it was shown that the hybridization may include polymer gold (AuNP). In the study, He X et al. examine the effect of polyhexamethylene biguanide polymer hybridized with AuNP and prove a promising synergistic activity of this drug delivery system to propagate wound healing infected with S. aureus [133].
Moreover, magnetic carboxymethyl cellulose-ε-poly-lysine hybrids were synthesized and used as matrix to anchor Ag NPs. This hybrid Ag NP complex shows promising antibacterial activity against S. aureus and E. coli and shows synergistic antibacterial activity for wound infection treatment [134].

5. Free Antibiotic VS Nanoantibiotic

Antibiotics are a substance that reduces the growth of germs, combats some diseases, and saves lives when administered properly. They are the basic pharmacological options for treating biofilm and planktonic infections [135,136].
Nonoantibiotic (nAbts) are pure antibiotic molecules that have been synthetically grown to an average diameter of ≤100 nm minimally at one dimension, or engineered NPs that encapsulate the antibiotic molecules.
Antibiotics frequently result in the death of bacteria by disrupting the proton driving force throughout the cell membrane, lowering the microbe ability to produce or store energy, blocking protein production, rupturing the structural components of the cell wall, etc. [137].
Multifunctional “intelligent” antimicrobials contained in NPs react to stimuli to interact with the surfaces of bacterial cell walls and membranes, improving entry through membranes and drug distribution to target sites. nAbts further have a target-specific, controlled release which can be administered in a single dose, unlike the majority of traditional antibiotics that require many doses in a systematic release [138].
In comparison to “free” antibiotics, the dosage of antibiotics administered via nanoparticle-based delivery systems has additional benefits, including decreased amount and frequency of the dose, sustained drug release that boosts drug efficiency, and targeted drug delivery to a specific site within bacterial cell [138,139].
When compared to molecular materials, NPs have a high surface-to-volume ratio and a unique surface area; as a result, these nanoscale particles have an extraordinary large contact area [140].
When antibiotics are combined with NPs, the antibiotic is transported to the desired locations and the NPs simultaneously activate a variety of antibacterial defenses. Therefore, NPs provide more functionalities compared to the effects of one medicine or the combination of various therapies for treating MDR strains [140].
Taking β-lactam antibiotics and β-lactam nAbts as an example, β-lactam antibiotics destroy microorganisms via numerous approaches, including (a) inhibiting the transpeptidase enzyme responsible for cross linkage of peptidoglycan in bacterial cell wall from functioning, (b) blocking the penicillin-binding proteins (PBPs), the enzymes responsible for synthesis of peptidoglycan in bacterial cell wall, and (c) destroying Ftsl (PBP3), an important protein complex required by living microorganisms [141].
The production of ROS by nAbts has been linked to DNA deterioration, protein denaturation, membrane malfunction, and deterioration of membrane stability [142].
The NPs linked to antibiotics can physically damage cellular structures by dissolving and liberating metal ions, resulting in biomechanical damage [143]. Furthermore, signal transmission inhibits ATPase activity and ribosomal subunit binding to tRNA; modifying metabolic activities include protein regulation, metabolism of lipids, carbs, and energy, as well as prevention of bacterial growth, leading to cell death [144,145,146,147]. The interaction of nanosized antibiotics with intracellular component of bacteria is critical in applications such as antimicrobial transportation, drug transporters, cell membrane infiltration to specific locations, and interruption of protein synthesis. As a result, nAbts are seen as a possible alternative to current antimicrobial resistance and treatment methods in clinical infections [148,149].

6. Mechanisms of Action of Nanoparticles (NPs)

It is challenging to pinpoint the specific mechanisms of action of NPs because the action is multifactorial in nature [150,151].
To battle bacteria, nanomaterial can use a variety of bactericidal methods, such as the production of reactive oxygen species (ROS), destruction of cell walls and membranes, the distribution of medicines via membrane fusion, and interacting with intracellular elements (e.g., DNA and ribosomes) (Figure 4). It is noted that nanomaterials’ special physico-chemical characteristics, particularly their chelation with bacterial cells, are determined through Van der Waals forces, receptor–ligand interactions, hydrophobic interactions, and electrostatic attractions [152].

6.1. Destruction of Cell Wall and Cell Membrane

The cell membrane of microorganisms has developed to act as a physical barrier to antimicrobials. Teichoic acids, which are found in Gram-positive bacteria’s cell walls, and lipopolysaccharide, which is present in Gram-negative bacteria’s outer membrane, both include phosphate or carboxyl groups that make the surfaces of the bacteria negatively charged. This intensely polar environment hinders hydrophobic antimicrobials’ ability to penetrate membranes, impairing their ability to combat microorganisms [152].
Through electrostatic adsorption to the cell wall, membrane depolarization, decrease in membrane permeability, and loss of membrane fluidity occur, resulting in disruption of energy transmission and cell death [9].
Besides that, a buildup of NPs causes “pits” to form in the bacterial cell wall. As a result, they can enter cells, altering their cell membranes and resulting in structural damage and cell death [153]. By interacting with the bacterial surfaces’ negative charges (through carboxyl or phosphate groups), positively charged ions produced by NPs have a greater bactericidal effect [154,155]. However, because Gram-positive bacteria have a thick coat of peptidoglycan, it is more difficult for nanoparticles (NPs) to enter the bacteria. As a result, NPs only interact with the bacterial surface [156].

6.2. Production of Reactive Oxygen Species (ROS)

ROS are byproduct results from oxidative metabolism. They influence cell development, signaling, survival, and death [146]. In addition, they have strong positive redox potential [157].
ROS include hydroxyl radicals (˙OH), superoxide radicals (O2−), singlet oxygen (O2), and hydrogen peroxide (H2O2). Different NPs generate various mixtures of ROS, which have different antibacterial characteristics. For instance, MgO NPs and ZnO NPs only produce the (O2−) radicals and a mixture of (H2O2) and the (˙OH) radicals, respectively, while Ag and Cu NPs generate all forms of ROS [154].
ROS are brought on by NPs or by disruption of the respiratory chain [157]. Usually, they are kept in low level by scavengers’ molecules as reduced glutathione [158].
In a typical environment, ROS generation and removal are proportional. However, under extreme stress, there is too much ROS generation, which leads to alteration in the cell membrane fluidity and results in bacterial damage [155]. Along with oxidative stress, ROS can disrupt macromolecules in the cell, resulting in lipid peroxidation, protein modification, enzyme inhibition, inhibition of electron transport chain and RNA or DNA damage (Figure 2).
It was reported that significant antimicrobial effects caused by production of ROS can be observed in the case of Ag [110,159,160], Cu [110,161], ZnO [115,162], TiO2 [118,163], and iron [164,165,166] NPs.

6.3. Binding to and Damaging Intracellular Component

Bacteria’s ability to function and survive depends on their cellular homoeostasis and intracellular signaling pathways. Cell death can result from the engineering of nanomaterials to obstruct these pathways. Changes in protein synthesis, DNA damage, and altered gene expression are some of these disruptions [167,168]. As an illustration, to create pyrimidine-capped AuNPs, 4,6-diamino-2-pyrimidinethiol (DAPT), an analogue of 2-pyrimidinethiol (found in E. coli), was added to AuNPs (Au-DAPT). MDR strains of Pseudomonas aeruginosa and E. coli were prevented from growing by these nanoparticles [144].

6.4. Destruction of Biofilm Architecture

NPs can destruct biofilm due to their high penetration power. They penetrate dense layers of biofilm (extracellular polysaccharide matrix), and once they evade biofilm, they interact with bacteria and exert bactericidal effect. Charge in NPs is greatly affecting the interaction and penetration of biofilm. For instance, positively charged or cationic NPs are firmly interacting with anionic matrix [169,170].

7. Synergistic Activity of Nanoantibiotics

When nanoparticles are coated or coupled with other substances, their activity can be significantly improved (Figure 5). In fact, utilizing nanoparticles in conjunction with antibiotics can help to decrease bacterial resistance. Antibiotics may be incorporated in nanoparticles or bonded to their surfaces, protecting Abs from chemicals and enzymes that would break them down. This protection may improve a drug’s therapeutic effectiveness. lowering dosage is required to improve treatment outcomes and reduce host hazard [171,172,173].
The use of nanocarriers can reduce resistance selection by delivering treatments that stimulate numerous modes of action and by targeting cargo release, preventing bacteria from being exposed to sub-minimal inhibitory doses of the drug [174]; In addition, when they serve as antibiotic carriers, penetration of bacterial cell walls becomes easier. The antibiotic then causes damage to the cell wall, allowing the nanoparticles and their complex to enter the body more easily [54].
In previous studies, when amoxicillin was coupled with AgNps, a noticeable drop in bacterial growth was observed [175], AgNps-ampicillin complex displays more antibacterial action than a single amoxicillin dose against S. aureus, E. coli, and K. mobilis [176], Enhanced antimicrobial action against P. aeruginosa was seen in vitro and in vivo when the gentamicin was loaded into poly(lactide-co-glycolide) (PLGA) nanoparticles [177]. When ampicillin was bonded to the interface of AuNPs and AgNPs, broad-spectrum bactericidal agents were created that bypass the resistance pathways of MDR strains of P. aeruginosa, Enterobacter aerogenes, and MRSA [171]. Increasing colistin activity against colistin-resistant E. coli by combining it with alginate nanoparticles and small molecules such as components of essential Oils, polyamines, lactic Acid [178], bimetallic nanoparticles (gold/silver), and core shell linezolid (Au@Ag@Lz) complexes shows good bactericidal action against all investigated pathogens, including MRSA [179].

7.1. Effect on Planktonic Bacteria

Planktonic bacteria are free-living bacteria [180]. Serious infectious conditions such as sepsis and keratitis are frequently caused by planktonic bacteria. The most serious group of planktonic bacteria are collectively called ESKAPE pathogens (Enterococcus, Staphylococcus, Klebsiella, Actinobacter, Pseudomonas, and Enterobacter), and they account for the majority of hospital-acquired infections, complicating the conditions of patients who are often immunocompromised [1,181,182].
Because these microorganisms produce resistance quickly even to the latest antibiotics, there are few treatment options for infections caused by them [182].
Because little to no resistance development is shown with nanomaterial-based techniques, nanoparticles can save therapeutic design in this regard [9,183,184].
Protein is the primary driver of bacterial life processes and is found in essential bacterial cell components such as cell walls, cell membranes, ribosomes, nucleic acid, etc. As a result, any of the above components can be destroyed and cause bacterial death [185].
The effectiveness of nanomaterials against the ESKAPE pathogens has been the subject of numerous studies: through disrupting cell membrane [111,117,186,187,188], interfering with protein [113,189,190,191,192], or by targeting nucleic acid [193,194,195].

7.2. Effect on Intracellular Bacteria

Bacteria can live inside of mammalian cells, resulting in recurrent systemic infections. For instance, Salmonella enterica is a classic facultative intracellular organism that annually causes potentially fatal food-borne infections in millions of people. Salmonella species have the ability to live and multiply within host cells, including macrophages [196,197]. Because many antibiotics are unable to cross the membranes of mammals and can actively be transported outside by the host cell, intracellular localization of bacteria makes treatment more challenging. Owing to nanomaterials’ capacity to enter eukaryotic cells and their high drug loading capacity, they can help to overcome this obstacle [198,199].
Another example of an intracellular microorganism which persists inside macrophages is Mycobacterium tuberculosis (MTb) and Mycobacterium avium [200,201,202,203]. The efficacy of nanoparticles against intracellular MTb species has been shown in multiple studies on topics such as the following: (a) biodegradable multimetallic microparticles including Ag NPs and ZnO NPs were created for pulmonary medication delivery to the endosomal pathway of MTb-infected macrophages [204]; (b) ZnONPs and the mixture MgONPs-ZnONPs have higher bactericide behavior and might have synergistic effects against MDR-MTb [116]; (c) the use of all trans retinoic acid-loaded nanoparticles in a host-directed therapy for TB, which targets the host’s immune system response rather than MTb directly, has promise for enhancing current treatments and reducing the emergence of MDR-MTb [107]; (d) PLGA NP loaded with various antibiotics (levofloxacin, linezolid, ethambutol, prothionamide, and pyrazinamide) show promising approach for MDR-MTb by enhancing drug efficacy and inducing innate bactericidal events in macrophages [205]. Other studies have proven the promising effect of NPs on other intracellular bacteria: (a) docosanoic acid solid lipid nanoparticles that were loaded with enrofloxacin raised the intracellular concentration of the drug by up to 40 times and improved killing of Salmonella within macrophages [206]; (b) colistin, a weakly diffusible antimicrobial agent, was transformed into liposomes complexed with a protein derived from bacteria to promote internalization into eukaryotic cells and deliver drugs with a high bioavailability [207]; (c) Listeria monocytogenes and P. aeruginosa were eliminated from inside invaded macrophages by gentamicin-loaded AuNPs coated with phosphatidylcholine [208].

7.3. Effect on Bacterial Biofilm

A biofilm is a network of thousands of bacteria that acts as a barrier against the human immune system, extreme conditions, and antibiotics [209].
Bacteria can grow in two different ways: as free-floating planktonic organisms or as sessile, surface-attached communities seen in biofilms, which are organized colonies enclosed in a self-produced extracellular polymeric matrix (EPS) [210,211].
Biofilm formation is a process initiated by planktonic (free-living) organisms aggregating on the outside of either living or inanimate items [212].
Approximately two-thirds of the biofilm’s volume is composed of EPS [213], which mostly consists of lipids, carbohydrates, proteins, and nucleic acids [209], giving bacteria a 3D protective structure. Bacteria implanted in the matrix can interact synergistically, communicate with one another, and transfer resistance genes [214]. Additionally, the lower oxygen and nutrition levels in the higher depth of the matrix lead to the creation of latent persister cells, which support antimicrobial tolerance and resistance [212,215]. The matrix is also rich in hydrophobic groups and negatively charged elements and 3D structure of EPS forming mesh-like structure containing pores filled with water, facilitating transmission between bacterial communities [216,217].
MDR biofilm infections represent an especially challenging treatment obstacle, and to combat biofilms, it is necessary to overcome the physical barrier produced by them [215,218,219].
Bacterial communities communicate with each other through autoinducer called quorum sensing (QS); therefore, biofilm eradication occurs through degrading EPS, QS, and killing of internal bacteria [220].
Nanoparticles show promising effect to overcome and eradicate MDR biofilm infections. The invasion of this highly stable polymeric matrix can be enhanced by optimizing the surface properties and designating the nanoparticles [25,221]. Important variables affecting the invasion and penetration of biofilm include size and electrostatic interactions. Generally, positively charged nanomaterials have an excellent penetration within the matrix, whereas uncharged nanomaterials smaller than 350 nm are more mobile through holes present in biofilms [222].
When nanomaterials invade biofilms, they can interact with bacteria and produce antimicrobial effects. It wase proved in previous studies that polymeric nano delivery systems, in which the antibiotic is encased in a formulation, have shown considerable promise in terms of facilitating a high local drug concentration at the site of infection, controlled drug release, and minimal drug degradation [223]. In another study, zinc oxide nanoparticles with pancreatin enzyme (ZnONPs-PK) have anti-bacterial and anti-biofilm activity and are potent to eradicate MRSA [224]. In a different method, a promising result was achieved when using prolonged release poly-lactic-co-glycolic acid (PLGA) micro- and nanoparticles containing ciprofloxacin against biofilms of S. aureus and P. aeruginosa [225].

8. Strengths and Challenges in the Application of NPs against MDR Infection

Due to the unique size and physical characters of NPs, they provide significant advantages over conventional antibiotics; however, their delivery method is still challenging. They provide sustained release system and targeted delivery of antibiotic. Therefore, small and reduced doses are the required result in order to decrease the frequency of dosing, host cell toxicity and emergence of resistance [226,227].
However, NPs systemic administration still has to handle a number of other issues and challenges, including additional analysis of NP interactions with cells, tissues, and organs, optimal dose, identification of suitable routes of administration, toxicity following both short-term and long-term exposure [227,228], and exact mechanism of cellular uptake. Moreover, prolonged exposure to NPs in the workplace may result in unanticipated health risks. Inhaling nanoparticles in the form of air pollutants is another method of secondary exposure to NPs. Sometimes, these inhaled nanoparticles can evade the immune system and spread throughout the body, causing systemic health problems. Moreover, intravenous administration of NPs lead to their accumulation in spleen, lung and bone marrow [229]. In addition, inhaled NPs can distribute through lung, heart, liver, spleen and brain due to their small size, large surface area and high absorption rate [230]. Administration of NP therapeutically may cause multiorgan nanotoxicity. In all toxic cases, NPs are linked to oxidative stress, which in turn causes hepatotoxicity and lung toxicity [231] and metabolic modifications such as β oxidation of fatty acid, glycolysis and reduced ketogenesis that occur through ROS and may be associated with hepatotoxicity and nephrotoxicity [232]. Therefore, due to previous challenges, no FDA-approved nAbts for systemic human use have been launched to date. Hence, the safety, toxicity, pharmacokinetic and pharmacodynamic profile of NP systems as well as the therapeutic efficacy measures used in clinical trials must be considered in future preclinical investigations [11,22,226,233]. Finally, the financial implications of these NP clinical translations regarding their therapeutic efficacy need to be evaluated [226,234].

9. Conclusions and Future Perspectives

The emergence and growth of MDR bacteria have shown to be a serious health issue that must be managed on a global scale. To treat persistent MDR planktonic bacterial and biofilm infections, nanomaterials offer a novel, “outside the box” strategy. Optimization of their physical characters, particularly size and surface charge, is essential to maximize their curative potential and decrease host hazard. Clinical use is currently limited by issues concerning the long-term effects of nanoparticles on the person and systemic safety. Moreover, metabolic, toxicity, stability issues and mechanism explanation on the gene level show that the NP effect on gene expression should be explained in detail in future studies. Additionally, the exact and detailed mechanism of interaction of NPs with biological systems should be explained in future trials to develop nanomaterials with favorable physicochemical properties that will allow them to be more responsive to varied biological settings for therapeutic advantages while having no negative effect. The field of nAbs will act as the next-generation medicines in near future to combat MDR bacteria.

Author Contributions

Conceptualization, H.F.H., Y.N.R., N.H.A.E.; literature search, data analysis, curation and visualization, H.F.H., Y.N.R., A.I.A.-H., E.A.A., B.B., N.H.A.E., S.Z., M.G.D.; writing—original draft preparation, H.F.H., Y.N.R., A.I.A.-H., E.A.A., B.B., N.H.A.E., S.Z., M.G.D.; writing—review and editing, H.F.H., Y.N.R., A.I.A.-H., E.A.A., B.B., N.H.A.E., S.Z., M.G.D.; funding acquisition, S.Z. and M.G.D. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. CDC. Antimicrobial (AR) Threats Report. Available online: https://www.cdc.gov/drugresistance/biggest-threats.html (accessed on 1 December 2022).
  2. Nageeb, W.M.; Hetta, H.F. The predictive potential of different molecular markers linked to amikacin susceptibility phenotypes in Pseudomonas aeruginosa. PLoS ONE 2022, 17, e0267396. [Google Scholar] [CrossRef] [PubMed]
  3. Algammal, A.M.; Alfifi, K.J.; Mabrok, M.; Alatawy, M.; Abdel-Moneam, D.A.; Alghamdi, S.; Azab, M.M.; Ibrahim, R.A.; Hetta, H.F.; El-Tarabili, R.M. Newly Emerging MDR B. cereus in Mugil seheli as the First Report Commonly Harbor nhe, hbl, cytK, and pc-plc Virulence Genes and bla1, bla2, tetA, and ermA Resistance Genes. Infect. Drug Resist. 2022, 15, 2167–2185. [Google Scholar] [CrossRef] [PubMed]
  4. Hamad, A.A.; Sharaf, M.; Hamza, M.A.; Selim, S.; Hetta, H.F.; El-Kazzaz, W. Investigation of the Bacterial Contamination and Antibiotic Susceptibility Profile of Bacteria Isolated from Bottled Drinking Water. Microbiol. Spectr. 2022, 10, e0151621. [Google Scholar] [CrossRef] [PubMed]
  5. Algammal, A.M.; Abo Hashem, M.E.; Alfifi, K.J.; Al-Otaibi, A.S.; Alatawy, M.; ElTarabili, R.M.; Abd El-Ghany, W.A.; Hetta, H.F.; Hamouda, A.M.; Elewa, A.A. Sequence Analysis, Antibiogram Profile, Virulence and Antibiotic Resistance Genes of XDR and MDR Gallibacterium anatis Isolated from Layer Chickens in Egypt. Infect. Drug Resist. 2022, 15, 4321–4334. [Google Scholar] [CrossRef]
  6. Meshaal, A.K.; Hetta, H.F.; Yahia, R.; Abualnaja, K.M.; Mansour, A.T.; Al-Kadmy, I.M.; Alghamdi, S.; Dablool, A.S.; Emran, T.B.; Sedky, H. In Vitro Antimicrobial Activity of Medicinal Plant Extracts against Some Bacterial Pathogens Isolated from Raw and Processed Meat. Life 2021, 11, 1178. [Google Scholar] [CrossRef]
  7. Rangel-López, L.; Zaragoza-Bastida, A.; Valladares-Carranza, B.; Peláez-Acero, A.; Sosa-Gutiérrez, C.G.; Hetta, H.F.; Batiha, G.E.-S.; Alqahtani, A.; Rivero-Perez, N. In Vitro Antibacterial Potential of Salix babylonica Extract against Bacteria that Affect Oncorhynchus mykiss and Oreochromis spp. Animals 2020, 10, 1340. [Google Scholar] [CrossRef]
  8. Ventola, C.L. The antibiotic resistance crisis: Part 1: Causes and threats. Pharm. Ther. 2015, 40, 277. [Google Scholar]
  9. Pelgrift, R.Y.; Friedman, A.J. Nanotechnology as a therapeutic tool to combat microbial resistance. Adv. Drug Deliv. Rev. 2013, 65, 1803–1815. [Google Scholar] [CrossRef]
  10. Teixeira, M.; Sanchez-Lopez, E.; Espina, M.; Calpena, A.; Silva, A.M.; Veiga, F.; Garcia, M.; Souto, E.B. Advances in antibiotic nanotherapy: Overcoming antimicrobial resistance. Emerg. Nanotechnologies Immunol. 2018, 21, 233–259. [Google Scholar]
  11. Yang, X.; Ye, W.; Qi, Y.; Ying, Y.; Xia, Z. Overcoming Multidrug Resistance in Bacteria Through Antibiotics Delivery in Surface-Engineered Nano-Cargos: Recent Developments for Future Nano-Antibiotics. Front. Bioeng. Biotechnol. 2021, 9, 696514. [Google Scholar] [CrossRef]
  12. Donadu, M.G.; Mazzarello, V.; Cappuccinelli, P.; Zanetti, S.; Madléna, M.; Nagy, Á.L.; Stájer, A.; Burián, K.; Gajdács, M. Relationship between the Biofilm-Forming Capacity and Antimicrobial Resistance in Clinical Acinetobacter baumannii Isolates: Results from a Laboratory-Based In Vitro Study. Microorganisms 2021, 9, 2384. [Google Scholar] [CrossRef]
  13. Usai, D.; Donadu, M.; Bua, A.; Molicotti, P.; Zanetti, S.; Piras, S.; Corona, P.; Ibba, R.; Carta, A. Enhancement of antimicrobial activity of pump inhibitors associating drugs. J. Infect. Dev. Ctries 2019, 13, 162–164. [Google Scholar] [CrossRef]
  14. Spengler, G.; Gajdács, M.; Donadu, M.G.; Usai, M.; Marchetti, M.; Ferrari, M.; Mazzarello, V.; Zanetti, S.; Nagy, F.; Kovács, R. Evaluation of the Antimicrobial and Antivirulent Potential of Essential Oils Isolated from Juniperus oxycedrus L. ssp. macrocarpa Aerial Parts. Microorganisms 2022, 10, 758. [Google Scholar] [CrossRef] [PubMed]
  15. Pinna, A.; Donadu, M.G.; Usai, D.; Dore, S.; Boscia, F.; Zanetti, S. In Vitro Antimicrobial Activity of a New Ophthalmic Solution Containing Hexamidine Diisethionate 0.05% (Keratosept). Cornea 2020, 39, 1415–1418. [Google Scholar] [CrossRef] [PubMed]
  16. Algammal, A.M.; Elsayed, M.E.; Hashem, H.R.; Ramadan, H.; Sheraba, N.S.; El-Diasty, E.M.; Abbas, S.M.; Hetta, H.F. Molecular and HPLC-based approaches for detection of aflatoxin B1 and ochratoxin A released from toxigenic Aspergillus species in processed meat. BMC Microbiol. 2021, 21, 1–10. [Google Scholar] [CrossRef] [PubMed]
  17. Horikoshi, S.; Serpone, N. Microwaves in Nanoparticle Synthesis: Fundamentals and Applications; John Wiley & Sons: Hoboken, NJ, USA, 2013. [Google Scholar]
  18. Abd El-Aziz, F.E.-Z.A.; Hetta, H.F.; Abdelhamid, B.N.; Abd Ellah, N.H. Antibacterial and wound-healing potential of PLGA/spidroin nanoparticles: A study on earthworms as a human skin model. Nanomedicine 2022, 17, 353–365. [Google Scholar] [CrossRef] [PubMed]
  19. Abdellatif, A.A.; Tawfeek, H.M.; Abdelfattah, A.; Batiha, G.E.-S.; Hetta, H.F. Recent updates in COVID-19 with emphasis on inhalation therapeutics: Nanostructured and targeting systems. J. Drug Deliv. Sci. Technol. 2021, 63, 102435. [Google Scholar] [CrossRef] [PubMed]
  20. Wasef, L.; Nassar, A.M.; El-Sayed, Y.S.; Samak, D.; Noreldin, A.; Elshony, N.; Saleh, H.; Elewa, Y.H.; Hassan, S.; Saati, A.A. The potential ameliorative impacts of cerium oxide nanoparticles against fipronil-induced hepatic steatosis. Sci. Rep. 2021, 11, 1310. [Google Scholar] [CrossRef]
  21. Eid, A.M.; Fouda, A.; Niedbała, G.; Hassan, S.E.-D.; Salem, S.S.; Abdo, A.M.; Hetta, F.H.; Shaheen, T.I. Endophytic Streptomyces laurentii mediated green synthesis of Ag-NPs with antibacterial and anticancer properties for developing functional textile fabric properties. Antibiotics 2020, 9, 641. [Google Scholar] [CrossRef]
  22. Mubeen, B.; Ansar, A.N.; Rasool, R.; Ullah, I.; Imam, S.S.; Alshehri, S.; Ghoneim, M.M.; Alzarea, S.I.; Nadeem, M.S.; Kazmi, I. Nanotechnology as a Novel Approach in Combating Microbes Providing an Alternative to Antibiotics. Antibiotics 2021, 10, 1473. [Google Scholar] [CrossRef]
  23. Tripathi, N.; Goshisht, M.K. Recent Advances and Mechanistic Insights into Antibacterial Activity, Antibiofilm Activity, and Cytotoxicity of Silver Nanoparticles. ACS Appl. Bio. Mater. 2022, 5, 1391–1463. [Google Scholar] [CrossRef] [PubMed]
  24. Tawre, M.S.; Shiledar, A.; Satpute, S.K.; Ahire, K.; Ghosh, S.; Pardesi, K. Synergistic and antibiofilm potential of Curcuma aromatica derived silver nanoparticles in combination with antibiotics against multidrug-resistant pathogens. Front. Chem. 2022, 10, 1029056. [Google Scholar] [CrossRef] [PubMed]
  25. Hetta, H.F.; Al-Kadmy, I.; Khazaal, S.S.; Abbas, S.; Suhail, A.; El-Mokhtar, M.A.; Ellah, N.H.A.; Ahmed, E.A.; Abd-Ellatief, R.B.; El-Masry, E.A. Antibiofilm and antivirulence potential of silver nanoparticles against multidrug-resistant Acinetobacter baumannii. Sci. Rep. 2021, 11, 10751. [Google Scholar] [CrossRef] [PubMed]
  26. Abdelraheem, W.M.; Khairy, R.M.; Zaki, A.I.; Zaki, S.H. Effect of ZnO nanoparticles on methicillin, vancomycin, linezolid resistance and biofilm formation in Staphylococcus aureus isolates. Ann. Clin. Microbiol. Antimicrob. 2021, 20, 54. [Google Scholar] [CrossRef] [PubMed]
  27. Hashem, A.H.; Al Abboud, M.A.; Alawlaqi, M.M.; Abdelghany, T.M.; Hasanin, M. Synthesis of nanocapsules based on biosynthesized nickel nanoparticles and potato starch: Antimicrobial, antioxidant, and anticancer activity. Starch Stärke 2022, 74, 2100165. [Google Scholar] [CrossRef]
  28. Hashem, A.H.; Salem, S.S. Green and ecofriendly biosynthesis of selenium nanoparticles using Urtica dioica (stinging nettle) leaf extract: Antimicrobial and anticancer activity. Biotechnol. J. 2022, 17, 2100432. [Google Scholar] [CrossRef] [PubMed]
  29. Abu-Elghait, M.; Hasanin, M.; Hashem, A.H.; Salem, S.S. Ecofriendly novel synthesis of tertiary composite based on cellulose and myco-synthesized selenium nanoparticles: Characterization, antibiofilm and biocompatibility. Int. J. Biol. Macromol. 2021, 175, 294–303. [Google Scholar] [CrossRef]
  30. Han, H.-W.; Patel, K.D.; Kwak, J.-H.; Jun, S.-K.; Jang, T.-S.; Lee, S.-H.; Knowles, J.C.; Kim, H.-W.; Lee, H.-H.; Lee, J.-H. Selenium nanoparticles as candidates for antibacterial substitutes and supplements against multidrug-resistant bacteria. Biomolecules 2021, 11, 1028. [Google Scholar] [CrossRef] [PubMed]
  31. Elbahnasawy, M.A.; Shehabeldine, A.M.; Khattab, A.M.; Amin, B.H.; Hashem, A.H. Green biosynthesis of silver nanoparticles using novel endophytic Rothia endophytica: Characterization and anticandidal activity. J. Drug Deliv. Sci. Technol. 2021, 62, 102401. [Google Scholar] [CrossRef]
  32. El-Batal, A.I.; Mosallam, F.M.; El-Sayyad, G.S. Synthesis of metallic silver nanoparticles by fluconazole drug and gamma rays to inhibit the growth of multidrug-resistant microbes. J. Clust. Sci. 2018, 29, 1003–1015. [Google Scholar] [CrossRef]
  33. Song, X.; Liu, P.; Liu, X.; Wang, Y.; Wei, H.; Zhang, J.; Yu, L.; Yan, X.; He, Z. Dealing with MDR bacteria and biofilm in the post-antibiotic era: Application of antimicrobial peptides-based nano-formulation. Mater. Sci. Eng. C 2021, 128, 112318. [Google Scholar] [CrossRef]
  34. Khalid, M.; El-Sawy, H.S. Polymeric nanoparticles: Promising platform for drug delivery. Int. J. Pharm. 2017, 528, 675–691. [Google Scholar]
  35. Qayyum, S.; Khan, A.U. Nanoparticles vs. biofilms: A battle against another paradigm of antibiotic resistance. MedChemComm 2016, 7, 1479–1498. [Google Scholar] [CrossRef]
  36. Liu, T.; Cui, Q.; Wu, Q.; Li, X.; Song, K.; Ge, D.; Guan, S. Mechanism study of bacteria killed on nanostructures. J. Phys. Chem. B 2019, 123, 8686–8696. [Google Scholar] [CrossRef] [PubMed]
  37. Wang, D.-Y.; Van der Mei, H.C.; Ren, Y.; Busscher, H.J.; Shi, L. Lipid-based antimicrobial delivery-systems for the treatment of bacterial infections. Front. Chem. 2020, 7, 872. [Google Scholar] [CrossRef] [Green Version]
  38. Saleh, H.; Nassar, A.M.; Noreldin, A.E.; Samak, D.; Elshony, N.; Wasef, L.; Elewa, Y.H.; Hassan, S.M.; Saati, A.A.; Hetta, H.F. Chemo-protective potential of cerium oxide nanoparticles against fipronil-induced oxidative stress, apoptosis, inflammation and reproductive dysfunction in male white albino rats. Molecules 2020, 25, 3479. [Google Scholar] [CrossRef]
  39. Adeyemi, O.S.; Arowolo, A.T.; Hetta, H.F.; Al-Rejaie, S.; Rotimi, D.; Batiha, G.E.-S. Apoferritin and Apoferritin-Capped Metal Nanoparticles Inhibit Arginine Kinase of Trypanosoma brucei. Molecules 2020, 25, 3432. [Google Scholar] [CrossRef]
  40. Chaturvedi, V.K.; Yadav, N.; Rai, N.K.; Ellah, N.H.A.; Bohara, R.A.; Rehan, I.F.; Marraiki, N.; Batiha, G.E.-S.; Hetta, H.F.; Singh, M. Pleurotus sajor-caju-mediated synthesis of silver and gold nanoparticles active against colon cancer cell lines: A new era of herbonanoceutics. Molecules 2020, 25, 3091. [Google Scholar] [CrossRef]
  41. Hetta, H.F.; Ahmed, E.A.; Hemdan, A.G.; El-Deek, H.E.; Abd-Elregal, S.; Abd Ellah, N.H. Modulation of rifampicin-induced hepatotoxicity using poly (lactic-co-glycolic acid) nanoparticles: A study on rat and cell culture models. Nanomedicine 2020, 15, 1375–1390. [Google Scholar] [CrossRef]
  42. Abd Ellah, N.H.; Ahmed, E.A.; Abd-Ellatief, R.B.; Ali, M.F.; Zahran, A.M.; Hetta, H.F. Metoclopramide nanoparticles modulate immune response in a diabetic rat model: Association with regulatory T cells and proinflammatory cytokines. Int. J. Nanomed. 2019, 14, 2383. [Google Scholar] [CrossRef] [Green Version]
  43. Blanco, E.; Shen, H.; Ferrari, M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat. Biotechnol. 2015, 33, 941–951. [Google Scholar] [CrossRef]
  44. Sharma, D.; Misba, L.; Khan, A.U. Antibiotics versus biofilm: An emerging battleground in microbial communities. Antimicrob. Resist. Infect. Control. 2019, 8, 76. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Ramasamy, M.; Lee, J. Recent nanotechnology approaches for prevention and treatment of biofilm-associated infections on medical devices. BioMed Res. Int. 2016, 2016, 1851242. [Google Scholar] [CrossRef]
  46. Lee, N.-Y.; Ko, W.-C.; Hsueh, P.-R. Nanoparticles in the treatment of infections caused by multidrug-resistant organisms. Front. Pharmacol. 2019, 10, 1153. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  47. Cheng, L.; Li, R.; Liu, G.; Zhang, Y.; Tang, X.; Wang, J.; Liu, H.; Qin, Y. Potential antibacterial mechanism of silver nanoparticles and the optimization of orthopedic implants by advanced modification technologies. Int. J. Nanomed. 2018, 13, 3311. [Google Scholar]
  48. Shobha, G.; Moses, V.; Ananda, S. Biological synthesis of copper nanoparticles and its impact. Int. J. Pharm. Sci. Invent 2014, 3, 6–28. [Google Scholar]
  49. Jaworski, S.; Wierzbicki, M.; Sawosz, E.; Jung, A.; Gielerak, G.; Biernat, J.; Jaremek, H.; Łojkowski, W.; Woźniak, B.; Wojnarowicz, J. Graphene oxide-based nanocomposites decorated with silver nanoparticles as an antibacterial agent. Nanoscale Res. Lett. 2018, 13, 116. [Google Scholar] [CrossRef] [Green Version]
  50. Anselmo, A.C.; Mitragotri, S. Nanoparticles in the clinic. Bioeng. Transl. Med. 2016, 1, 10–29. [Google Scholar] [CrossRef] [PubMed]
  51. Yetisgin, A.A.; Cetinel, S.; Zuvin, M.; Kosar, A.; Kutlu, O. Therapeutic nanoparticles and their targeted delivery applications. Molecules 2020, 25, 2193. [Google Scholar] [CrossRef] [PubMed]
  52. Abd Ellah, N.H.; Gad, S.F.; Muhammad, K.; E Batiha, G.; Hetta, H.F. Nanomedicine as a promising approach for diagnosis, treatment and prophylaxis against COVID-19. Nanomedicine 2020, 15, 2085–2102. [Google Scholar] [CrossRef]
  53. Mba, I.E.; Nweze, E.I. The use of nanoparticles as alternative therapeutic agents against Candida infections: An up-to-date overview and future perspectives. World J. Microbiol. Biotechnol. 2020, 36, 163. [Google Scholar] [CrossRef] [PubMed]
  54. Mba, I.E.; Sharndama, H.C.; Osondu-Chuka, G.O.; Okeke, O.P. Immunobiology and nanotherapeutics of severe acute respiratory syndrome 2 (SARS-CoV-2): A current update. Infect. Dis. 2021, 53, 559–580. [Google Scholar] [CrossRef]
  55. Abd Ellah, N.H.; Tawfeek, H.M.; John, J.; Hetta, H.F. Nanomedicine as a future therapeutic approach for Hepatitis C virus. Nanomedicine 2019, 14, 1471–1491. [Google Scholar] [CrossRef] [PubMed]
  56. Sayad, R.; Abdelsabour, H.A.; Farhat, S.M.; Omer, N.G.; Ahmed, M.M.; Elsayh, I.K.; Ibrahim, I.H.; Algammal, A.M.; AL-Kadmy, I.M.S.; Batiha, G.E.-S.; et al. Applications of nanotechnology in the fight against coronavirus disease 2019. Rev. Res. Med. Microbiol. 2019. [Google Scholar] [CrossRef]
  57. Abid, S.A.; Muneer, A.A.; Al-Kadmy, I.M.; Sattar, A.A.; Beshbishy, A.M.; Batiha, G.E.-S.; Hetta, H.F. Biosensors as a future diagnostic approach for COVID-19. Life Sci. 2021, 273, 119117. [Google Scholar] [CrossRef]
  58. Liao, S.; Zhang, Y.; Pan, X.; Zhu, F.; Jiang, C.; Liu, Q.; Cheng, Z.; Dai, G.; Wu, G.; Wang, L. Antibacterial activity and mechanism of silver nanoparticles against multidrug-resistant Pseudomonas aeruginosa. Int. J. Nanomed. 2019, 14, 1469. [Google Scholar] [CrossRef] [Green Version]
  59. Möhler, J.S.; Sim, W.; Blaskovich, M.A.; Cooper, M.A.; Ziora, Z.M. Silver bullets: A new lustre on an old antimicrobial agent. Biotechnol. Adv. 2018, 36, 1391–1411. [Google Scholar] [CrossRef] [Green Version]
  60. Merrifield, R.C.; Stephan, C.; Lead, J.R. Single-particle inductively coupled plasma mass spectroscopy analysis of size and number concentration in mixtures of monometallic and bimetallic (core-shell) nanoparticles. Talanta 2017, 162, 130–134. [Google Scholar] [CrossRef] [Green Version]
  61. Rajeshkumar, S.; Bharath, L. Mechanism of plant-mediated synthesis of silver nanoparticles–a review on biomolecules involved, characterisation and antibacterial activity. Chem. -Biol. Interact. 2017, 273, 219–227. [Google Scholar] [CrossRef]
  62. MacGowan, A.; Macnaughton, E. Antibiotic resistance. Medicine 2017, 45, 622–628. [Google Scholar] [CrossRef]
  63. El-Mokhtar, M.A.; Hetta, H.F. Ambulance vehicles as a source of multidrug-resistant infections: A multicenter study in Assiut City, Egypt. Infect. Drug Resist. 2018, 11, 587. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Munita, J.M.; Arias, C.A. Mechanisms of antibiotic resistance. Microbiol. Spectr. 2016, 4, 15. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Alekshun, M.N.; Levy, S.B. Molecular mechanisms of antibacterial multidrug resistance. Cell 2007, 128, 1037–1050. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  66. El-Kazzaz, W.; Metwally, L.; Yahia, R.; Al-Harbi, N.; El-Taher, A.; Hetta, H.F. Antibiogram, prevalence of OXA carbapenemase encoding genes, and RAPD-genotyping of multidrug-resistant Acinetobacter baumannii incriminated in hidden community-acquired infections. Antibiotics 2020, 9, 603. [Google Scholar] [CrossRef]
  67. Abd El-Baky, R.M.; Farhan, S.M.; Ibrahim, R.A.; Mahran, K.M.; Hetta, H.F. Antimicrobial resistance pattern and molecular epidemiology of ESBL and MBL producing Acinetobacter baumannii isolated from hospitals in Minia, Egypt. Alex. J. Med. 2020, 56, 4–13. [Google Scholar] [CrossRef]
  68. Makharita, R.R.; El-Kholy, I.; Hetta, H.F.; Abdelaziz, M.H.; Hagagy, F.I.; Ahmed, A.A.; Algammal, A.M. Antibiogram and genetic characterization of carbapenem-resistant gram-negative pathogens incriminated in healthcare-associated infections. Infect. Drug Resist. 2020, 13, 3991. [Google Scholar] [CrossRef] [PubMed]
  69. Farhan, S.M.; Ibrahim, R.A.; Mahran, K.M.; Hetta, H.F.; Abd El-Baky, R.M. Antimicrobial resistance pattern and molecular genetic distribution of metallo-β-lactamases producing Pseudomonas aeruginosa isolated from hospitals in Minia, Egypt. Infect. Drug Resist. 2019, 12, 2125. [Google Scholar] [CrossRef] [Green Version]
  70. Algammal, A.M.; Hetta, H.F.; Elkelish, A.; Alkhalifah, D.H.H.; Hozzein, W.N.; Batiha, G.E.-S.; El Nahhas, N.; Mabrok, M.A. Methicillin-Resistant Staphylococcus aureus (MRSA): One health perspective approach to the bacterium epidemiology, virulence factors, antibiotic-resistance, and zoonotic impact. Infect. Drug Resist. 2020, 13, 3255. [Google Scholar] [CrossRef]
  71. Kareem, S.M.; Al-Kadmy, I.M.; Kazaal, S.S.; Ali, A.N.M.; Aziz, S.N.; Makharita, R.R.; Algammal, A.M.; Al-Rejaie, S.; Behl, T.; Batiha, G.E.-S. Detection of gyra and parc mutations and prevalence of plasmid-mediated quinolone resistance genes in Klebsiella pneumoniae. Infect. Drug Resist. 2021, 14, 555. [Google Scholar] [CrossRef]
  72. Al-Kadmy, I.M.; Ibrahim, S.A.; Al-Saryi, N.; Aziz, S.N.; Besinis, A.; Hetta, H.F. Prevalence of genes involved in colistin resistance in Acinetobacter baumannii: First report from Iraq. Microb. Drug Resist. 2020, 26, 616–622. [Google Scholar] [CrossRef]
  73. Abd El-Baky, R.M.; Masoud, S.M.; Mohamed, D.S.; Waly, N.G.; Shafik, E.A.; Mohareb, D.A.; Elkady, A.; Elbadr, M.M.; Hetta, H.F. Prevalence and some possible mechanisms of colistin resistance among multidrug-resistant and extensively drug-resistant Pseudomonas aeruginosa. Infect. Drug Resist. 2020, 13, 323. [Google Scholar] [CrossRef] [Green Version]
  74. Gupta, A.; Saleh, N.M.; Das, R.; Landis, R.F.; Bigdeli, A.; Motamedchaboki, K.; Campos, A.R.; Pomeroy, K.; Mahmoudi, M.; Rotello, V.M. Synergistic antimicrobial therapy using nanoparticles and antibiotics for the treatment of multidrug-resistant bacterial infection. Nano Futures 2017, 1, 015004. [Google Scholar] [CrossRef]
  75. Gupta, D.; Singh, A.; Khan, A.U. Nanoparticles as efflux pump and biofilm inhibitor to rejuvenate bactericidal effect of conventional antibiotics. Nanoscale Res. Lett. 2017, 12, 454. [Google Scholar] [CrossRef] [PubMed]
  76. Abd El-Baky, R.M.; Sandle, T.; John, J.; Abuo-Rahma, G.E.-D.A.; Hetta, H.F. A novel mechanism of action of ketoconazole: Inhibition of the NorA efflux pump system and biofilm formation in multidrug-resistant Staphylococcus aureus. Infect. Drug Resist. 2019, 12, 1703. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. Ovung, A.; Bhattacharyya, J. Sulfonamide drugs: Structure, antibacterial property, toxicity, and biophysical interactions. Biophys. Rev. 2021, 13, 259–272. [Google Scholar] [CrossRef]
  78. Blair, J.; Webber, M.A.; Baylay, A.J.; Ogbolu, D.O.; Piddock, L.J. Molecular mechanisms of antibiotic resistance. Nat. Rev. Microbiol. 2015, 13, 42–51. [Google Scholar] [CrossRef]
  79. Hurdle, J.G.; O’neill, A.J.; Chopra, I.; Lee, R.E. Targeting bacterial membrane function: An underexploited mechanism for treating persistent infections. Nat. Rev. Microbiol. 2011, 9, 62–75. [Google Scholar] [CrossRef] [Green Version]
  80. Tseng, B.S.; Zhang, W.; Harrison, J.J.; Quach, T.P.; Song, J.L.; Penterman, J.; Singh, P.K.; Chopp, D.L.; Packman, A.I.; Parsek, M.R. The extracellular matrix protects P seudomonas aeruginosa biofilms by limiting the penetration of tobramycin. Environ. Microbiol. 2013, 15, 2865–2878. [Google Scholar]
  81. Khalil, M.A.; Ahmed, F.A.; Elkhateeb, A.F.; Mahmoud, E.E.; Ahmed, M.I.; Ahmed, R.I.; Hosni, A.; Alghamdi, S.; Kabrah, A.; Dablool, A.S. Virulence characteristics of biofilm-forming acinetobacter baumannii in clinical isolates using a Galleria Mellonella Model. Microorganisms 2021, 9, 2365. [Google Scholar] [CrossRef]
  82. Liu, J.; Gefen, O.; Ronin, I.; Bar-Meir, M.; Balaban, N.Q. Effect of tolerance on the evolution of antibiotic resistance under drug combinations. Science 2020, 367, 200–204. [Google Scholar] [CrossRef] [PubMed]
  83. Torky, H.A.; Saad, H.M.; Khaliel, S.A.; Kassih, A.T.; Sabatier, J.-M.; Batiha, G.E.-S.; Hetta, H.F.; Elghazaly, E.M.; De Waard, M. Isolation and Molecular Characterization of Corynebacterium pseudotuberculosis: Association with Proinflammatory Cytokines in Caseous Lymphadenitis Pyogranulomas. Animals 2023, 13, 296. [Google Scholar] [CrossRef] [PubMed]
  84. Mabrok, M.; Algammal, A.; Sivaramasamy, E.; Hetta, H.F.; Atwah, B.; Alghamdi, S.; Fawzy, A.; Avendaño-Herrera, R.; Rodkhum, C. Tenacibaculosis caused by Tenacibaculum maritimum: Updated knowledge of this marine bacterial fish pathogen. Front. Cell. Infect. Microbiol. 2023, 1862, 1068000. [Google Scholar] [CrossRef] [PubMed]
  85. Salah, M.; Badr, G.; Hetta, H.F.; Khalifa, W.A.; Shoreit, A.A. Fig latex inhibits the growth of pathogenic bacteria invading human diabetic wounds and accelerates wound closure in diabetic mice. Sci. Rep. 2022, 12, 21852. [Google Scholar] [CrossRef] [PubMed]
  86. Morgan, D.J.; Okeke, I.N.; Laxminarayan, R.; Perencevich, E.N.; Weisenberg, S. Non-prescription antimicrobial use worldwide: A systematic review. Lancet Infect. Dis. 2011, 11, 692–701. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. World Health Organization. Antibiotic Resistance: Multi-Country Public Awareness Survey; World Health Organization: Geneva, Switzerland, 2015. [Google Scholar]
  88. Algammal, A.M.; Mabrok, M.; Sivaramasamy, E.; Youssef, F.M.; Atwa, M.H.; El-Kholy, A.W.; Hetta, H.F.; Hozzein, W.N. Emerging MDR-Pseudomonas aeruginosa in fish commonly harbor oprL and toxA virulence genes and blaTEM, blaCTX-M, and tetA antibiotic-resistance genes. Sci. Rep. 2020, 10, 15961. [Google Scholar] [CrossRef]
  89. Roca, I.; Akova, M.; Baquero, F.; Carlet, J.; Cavaleri, M.; Coenen, S.; Cohen, J.; Findlay, D.; Gyssens, I.; Heure, O. The global threat of antimicrobial resistance: Science for intervention. New Microbes New Infect. 2015, 6, 22–29. [Google Scholar] [CrossRef]
  90. Algammal, A.M.; Hashem, H.R.; Alfifi, K.J.; Hetta, H.F.; Sheraba, N.S.; Ramadan, H.; El-Tarabili, R.M. atpD gene sequencing, multidrug resistance traits, virulence-determinants, and antimicrobial resistance genes of emerging XDR and MDR-Proteus mirabilis. Sci. Rep. 2021, 11, 9476. [Google Scholar] [CrossRef]
  91. Algammal, A.M.; Hetta, H.F.; Batiha, G.E.; Hozzein, W.N.; El Kazzaz, W.M.; Hashem, H.R.; Tawfik, A.M.; El-Tarabili, R.M. Virulence-determinants and antibiotic-resistance genes of MDR-E. coli isolated from secondary infections following FMD-outbreak in cattle. Sci. Rep. 2020, 10, 19779. [Google Scholar] [CrossRef]
  92. Elkhawaga, A.A.; Hetta, H.F.; Osman, N.S.; Hosni, A.; El-Mokhtar, M.A. Emergence of Cronobacter sakazakii in cases of neonatal sepsis in upper Egypt: First report in North Africa. Front. Microbiol. 2020, 11, 215. [Google Scholar] [CrossRef] [Green Version]
  93. Lebeaux, D.; Chauhan, A.; Rendueles, O.; Beloin, C. From in vitro to in vivo models of bacterial biofilm-related infections. Pathogens 2013, 2, 288–356. [Google Scholar] [CrossRef] [Green Version]
  94. Saginur, R.; StDenis, M.; Ferris, W.; Aaron, S.D.; Chan, F.; Lee, C.; Ramotar, K. Multiple combination bactericidal testing of staphylococcal biofilms from implant-associated infections. Antimicrob. Agents Chemother. 2006, 50, 55–61. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  95. Hall-Stoodley, L.; Costerton, J.W.; Stoodley, P. Bacterial biofilms: From the natural environment to infectious diseases. Nat. Rev. Microbiol. 2004, 2, 95–108. [Google Scholar] [CrossRef] [PubMed]
  96. Hall, C.W.; Mah, T.-F. Molecular mechanisms of biofilm-based antibiotic resistance and tolerance in pathogenic bacteria. FEMS Microbiol. Rev. 2017, 41, 276–301. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  97. Tanwar, J.; Das, S.; Fatima, Z.; Hameed, S. Multidrug Resistance: An Emerging Crisis. Interdiscip. Perspect. Infect. Dis. 2014, 2014, 541340. [Google Scholar] [CrossRef] [Green Version]
  98. Yin, M.; Yang, M.; Yan, D.; Yang, L.; Wan, X.; Xiao, J.; Yao, Y.; Luo, J. Surface-Charge-Switchable and Size-Transformable Thermosensitive Nanocomposites for Chemo-Photothermal Eradication of Bacterial Biofilms in Vitro and in Vivo. ACS Appl. Mater. Interfaces 2022, 14, 8847–8864. [Google Scholar] [CrossRef] [PubMed]
  99. Lu, B.; Hu, E.; Xie, R.; Yu, K.; Lu, F.; Bao, R.; Wang, C.; Lan, G.; Dai, F. Magnetically Guided Nanoworms for Precise Delivery to Enhance In Situ Production of Nitric Oxide to Combat Focal Bacterial Infection In Vivo. ACS Appl. Mater. Interfaces 2021, 13, 22225–22239. [Google Scholar] [CrossRef] [PubMed]
  100. Zylberberg, C.; Matosevic, S. Pharmaceutical liposomal drug delivery: A review of new delivery systems and a look at the regulatory landscape. Drug Deliv. 2016, 23, 3319–3329. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  101. Lemière, J.; Carvalho, K.; Sykes, C. Cell-Sized Liposomes That Mimic Cell Motility and the Cell Cortex. In Methods in Cell Biology; Elsevier: Amsterdam, The Netherlands, 2015; Volume 128, pp. 271–285. [Google Scholar]
  102. Shek, P.; Yung, B.; Stanacev, N. Comparison between multilamellar and unilamellar liposomes in enhancing antibody formation. Immunology 1983, 49, 37. [Google Scholar]
  103. Bassetti, M.; Vena, A.; Russo, A.; Peghin, M. Inhaled Liposomal Antimicrobial Delivery in Lung Infections. Drugs 2020, 80, 1309–1318. [Google Scholar] [CrossRef]
  104. Amreddy, N.; Babu, A.; Muralidharan, R.; Panneerselvam, J.; Srivastava, A.; Ahmed, R.; Mehta, M.; Munshi, A.; Ramesh, R. Recent advances in nanoparticle-based cancer drug and gene delivery. Adv. Cancer Res. 2018, 137, 115–170. [Google Scholar] [PubMed]
  105. Sánchez, A.; Mejía, S.P.; Orozco, J. Recent Advances in Polymeric Nanoparticle-Encapsulated Drugs against Intracellular Infections. Molecules 2020, 25, 3760. [Google Scholar] [CrossRef] [PubMed]
  106. Saneja, A.; Kumar, R.; Mintoo, M.J.; Dubey, R.D.; Sangwan, P.L.; Mondhe, D.M.; Panda, A.K.; Gupta, P.N. Gemcitabine and betulinic acid co-encapsulated PLGA− PEG polymer nanoparticles for improved efficacy of cancer chemotherapy. Mater. Sci. Eng. C 2019, 98, 764–771. [Google Scholar] [CrossRef] [PubMed]
  107. Bahlool, A.Z.; Fattah, S.; O’Sullivan, A.; Cavanagh, B.; MacLoughlin, R.; Keane, J.; O’Sullivan, M.P.; Cryan, S.A. Development of Inhalable ATRA-Loaded PLGA Nanoparticles as Host-Directed Immunotherapy against Tuberculosis. Pharmaceutics 2022, 14, 1745. [Google Scholar] [CrossRef] [PubMed]
  108. Sherje, A.P.; Jadhav, M.; Dravyakar, B.R.; Kadam, D. Dendrimers: A versatile nanocarrier for drug delivery and targeting. Int. J. Pharm. 2018, 548, 707–720. [Google Scholar] [CrossRef]
  109. Ghezzi, M.; Pescina, S.; Padula, C.; Santi, P.; Del Favero, E.; Cantù, L.; Nicoli, S. Polymeric micelles in drug delivery: An insight of the techniques for their characterization and assessment in biorelevant conditions. J. Control. Release Off. J. Control. Release Soc. 2021, 332, 312–336. [Google Scholar] [CrossRef]
  110. Ameh, T.; Gibb, M.; Stevens, D.; Pradhan, S.H.; Braswell, E.; Sayes, C.M. Silver and Copper Nanoparticles Induce Oxidative Stress in Bacteria and Mammalian Cells. Nanomaterials 2022, 12, 2402. [Google Scholar] [CrossRef]
  111. Haidari, H.; Bright, R.; Kopecki, Z.; Zilm, P.S.; Garg, S.; Cowin, A.J.; Vasilev, K.; Goswami, N. Polycationic Silver Nanoclusters Comprising Nanoreservoirs of Ag+ Ions with High Antimicrobial and Antibiofilm Activity. ACS Appl. Mater. Interfaces 2021, 14, 390–403. [Google Scholar] [CrossRef]
  112. Al Hagbani, T.; Rizvi, S.M.D.; Hussain, T.; Mehmood, K.; Rafi, Z.; Moin, A.; Abu Lila, A.S.; Alshammari, F.; Khafagy, E.S.; Rahamathulla, M.; et al. Cefotaxime Mediated Synthesis of Gold Nanoparticles: Characterization and Antibacterial Activity. Polymers 2022, 14, 771. [Google Scholar] [CrossRef]
  113. Wang, L.; Zheng, W.; Li, S.; Zhong, L.; Jiang, X. Aminophenol-Decorated Gold Nanoparticles for Curing Bacterial Infections. Nano Lett. 2022, 22, 3576–3582. [Google Scholar] [CrossRef]
  114. Periakaruppan, R.; S, M.P.; C, P.; P, R.; S, G.R.; Danaraj, J. Biosynthesis of Silica Nanoparticles Using the Leaf Extract of Punica granatum and Assessment of Its Antibacterial Activities Against Human Pathogens. Appl. Biochem. Biotechnol. 2022, 194, 5594–5605. [Google Scholar] [CrossRef]
  115. Krishnamoorthy, R.; Athinarayanan, J.; Periyasamy, V.S.; Alshuniaber, M.A.; Alshammari, G.; Hakeem, M.J.; Ahmed, M.A.; Alshatwi, A.A. Antibacterial Mechanisms of Zinc Oxide Nanoparticle against Bacterial Food Pathogens Resistant to Beta-Lactam Antibiotics. Molecules 2022, 27, 2489. [Google Scholar] [CrossRef]
  116. Yaghubi Kalurazi, T.; Jafari, A. Evaluation of magnesium oxide and zinc oxide nanoparticles against multi-drug-resistance Mycobacterium tuberculosis. Indian J. Tuberc. 2021, 68, 195–200. [Google Scholar] [CrossRef] [PubMed]
  117. Lin, Y.; Liu, X.; Liu, Z.; Xu, Y. Visible-Light-Driven Photocatalysis-Enhanced Nanozyme of TiO2 Nanotubes@ MoS2 Nanoflowers for Efficient Wound Healing Infected with Multidrug-Resistant Bacteria. Small 2021, 17, 2103348. [Google Scholar] [CrossRef]
  118. Eymard-Vernain, E.; Luche, S.; Rabilloud, T.; Lelong, C. ZnO and TiO2 nanoparticles alter the ability of Bacillus subtilis to fight against a stress. PLoS ONE 2020, 15, e0240510. [Google Scholar] [CrossRef]
  119. Younis, A.B.; Haddad, Y.; Kosaristanova, L.; Smerkova, K. Titanium dioxide nanoparticles: Recent progress in antimicrobial applications. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnology 2022, e1860. [Google Scholar] [CrossRef] [PubMed]
  120. Gilbertson, L.M.; Albalghiti, E.M.; Fishman, Z.S.; Perreault, F.; Corredor, C.; Posner, J.D.; Elimelech, M.; Pfefferle, L.D.; Zimmerman, J.B. Shape-Dependent Surface Reactivity and Antimicrobial Activity of Nano-Cupric Oxide. Environ. Sci. Technol. 2016, 50, 3975–3984. [Google Scholar] [CrossRef]
  121. Fonseca, S.; Cayer, M.P.; Ahmmed, K.M.T.; Khadem-Mohtaram, N.; Charette, S.J.; Brouard, D. Characterization of the Antibacterial Activity of an SiO(2) Nanoparticular Coating to Prevent Bacterial Contamination in Blood Products. Antibiotics 2022, 11, 107. [Google Scholar] [CrossRef]
  122. Jiang, Y.; Huo, S.; Hardie, J.; Liang, X.-J.; Rotello, V.M. Progress and perspective of inorganic nanoparticle-based siRNA delivery systems. Expert Opin. Drug Deliv. 2016, 13, 547–559. [Google Scholar] [CrossRef] [Green Version]
  123. Marcato, P.D.; Durán, N. New aspects of nanopharmaceutical delivery systems. J. Nanosci. Nanotechnol. 2008, 8, 2216–2229. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  124. Kassem, A.; Ayoub, G.M.; Malaeb, L. Antibacterial activity of chitosan nano-composites and carbon nanotubes: A review. Sci. Total Environ. 2019, 668, 566–576. [Google Scholar] [CrossRef] [PubMed]
  125. Noor, M.M.; Santana-Pereira, A.L.R.; Liles, M.R.; Davis, V.A. Dispersant Effects on Single-Walled Carbon Nanotube Antibacterial Activity. Molecules 2022, 27, 1606. [Google Scholar] [CrossRef]
  126. Ang, C.W.; Tan, L.; Qu, Z.; West, N.P.; Cooper, M.A.; Popat, A.; Blaskovich, M.A.T. Mesoporous Silica Nanoparticles Improve Oral Delivery of Antitubercular Bicyclic Nitroimidazoles. ACS Biomater. Sci. Eng. 2022, 8, 4196–4206. [Google Scholar] [CrossRef]
  127. Alandiyjany, M.N.; Abdelaziz, A.S.; Abdelfattah-Hassan, A.; Hegazy, W.A.H.; Hassan, A.A.; Elazab, S.T.; Mohamed, E.A.A.; El-Shetry, E.S.; Saleh, A.A.; ElSawy, N.A.; et al. Novel In Vivo Assessment of Antimicrobial Efficacy of Ciprofloxacin Loaded Mesoporous Silica Nanoparticles against Salmonella typhimurium Infection. Pharmaceuticals 2022, 15, 357. [Google Scholar] [CrossRef] [PubMed]
  128. Sánchez-Salcedo, S.; García, A.; González-Jiménez, A.; Vallet-Regí, M. Antibacterial effect of 3D printed mesoporous bioactive glass scaffolds doped with metallic silver nanoparticles. Acta Biomater. 2022, 155, 654–666. [Google Scholar] [CrossRef] [PubMed]
  129. Zafar, A.; Alruwaili, N.K.; Imam, S.S.; Alsaidan, O.A.; Ahmed, M.M.; Yasir, M.; Warsi, M.H.; Alquraini, A.; Ghoneim, M.M.; Alshehri, S. Development and Optimization of Hybrid Polymeric Nanoparticles of Apigenin: Physicochemical Characterization, Antioxidant Activity and Cytotoxicity Evaluation. Sensors 2022, 22, 1364. [Google Scholar] [CrossRef]
  130. Khalili, L.; Dehghan, G.; Sheibani, N.; Khataee, A. Smart active-targeting of lipid-polymer hybrid nanoparticles for therapeutic applications: Recent advances and challenges. Int. J. Biol. Macromol. 2022, 213, 166–194. [Google Scholar] [CrossRef] [PubMed]
  131. Elhassan, E.; Devnarain, N.; Mohammed, M.; Govender, T.; Omolo, C.A. Engineering hybrid nanosystems for efficient and targeted delivery against bacterial infections. J. Control. Release Off. J. Control. Release Soc. 2022, 351, 598–622. [Google Scholar] [CrossRef]
  132. Zhang, R.X.; Ahmed, T.; Li, L.Y.; Li, J.; Abbasi, A.Z.; Wu, X.Y. Design of nanocarriers for nanoscale drug delivery to enhance cancer treatment using hybrid polymer and lipid building blocks. Nanoscale 2017, 9, 1334–1355. [Google Scholar] [CrossRef]
  133. He, X.; Dai, L.; Ye, L.; Sun, X.; Enoch, O.; Hu, R.; Zan, X.; Lin, F.; Shen, J. A Vehicle-Free Antimicrobial Polymer Hybrid Gold Nanoparticle as Synergistically Therapeutic Platforms for Staphylococcus aureus Infected Wound Healing. Adv. Sci. 2022, 9, e2105223. [Google Scholar] [CrossRef]
  134. Jia, H.; Zeng, X.; Fan, S.; Cai, R.; Wang, Z.; Yuan, Y.; Yue, T. Silver nanoparticles anchored magnetic self-assembled carboxymethyl cellulose-ε-polylysine hybrids with synergetic antibacterial activity for wound infection therapy. Int. J. Biol. Macromol. 2022, 210, 703–715. [Google Scholar] [CrossRef]
  135. Cascioferro, S.; Carbone, D.; Parrino, B.; Pecoraro, C.; Giovannetti, E.; Cirrincione, G.; Diana, P. Therapeutic strategies to counteract antibiotic resistance in MRSA biofilm-associated infections. ChemMedChem 2021, 16, 65–80. [Google Scholar] [CrossRef]
  136. Makabenta, J.M.V.; Nabawy, A.; Li, C.-H.; Schmidt-Malan, S.; Patel, R.; Rotello, V.M. Nanomaterial-based therapeutics for antibiotic-resistant bacterial infections. Nat. Rev. Microbiol. 2021, 19, 23–36. [Google Scholar] [CrossRef] [PubMed]
  137. Kohanski, M.A.; Dwyer, D.J.; Collins, J.J. How antibiotics kill bacteria: From targets to networks. Nat. Rev. Microbiol. 2010, 8, 423–435. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  138. Mamun, M.M.; Sorinolu, A.J.; Munir, M.; Vejerano, E.P. Nanoantibiotics: Functions and properties at the nanoscale to combat antibiotic resistance. Front. Chem. 2021, 9, 687660. [Google Scholar] [CrossRef] [PubMed]
  139. Yeh, Y.-C.; Huang, T.-H.; Yang, S.-C.; Chen, C.-C.; Fang, J.-Y. Nano-based drug delivery or targeting to eradicate bacteria for infection mitigation: A review of recent advances. Front. Chem. 2020, 8, 286. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  140. Zaidi, S.; Misba, L.; Khan, A.U. Nano-therapeutics: A revolution in infection control in post antibiotic era. Nanomed. Nanotechnol. Biol. Med. 2017, 13, 2281–2301. [Google Scholar] [CrossRef]
  141. Chung, H.S.; Yao, Z.; Goehring, N.W.; Kishony, R.; Beckwith, J.; Kahne, D. Rapid beta-lactam-induced lysis requires successful assembly of the cell division machinery. Proc. Natl. Acad. Sci. USA 2009, 106, 21872–21877. [Google Scholar] [CrossRef]
  142. Zhang, Y.M.; Rock, C.O. Membrane lipid homeostasis in bacteria. Nat. Reviews. Microbiol. 2008, 6, 222–233. [Google Scholar] [CrossRef]
  143. Nel, A.E.; Mädler, L.; Velegol, D.; Xia, T.; Hoek, E.M.; Somasundaran, P.; Klaessig, F.; Castranova, V.; Thompson, M. Understanding biophysicochemical interactions at the nano-bio interface. Nat. Mater. 2009, 8, 543–557. [Google Scholar] [CrossRef]
  144. Zhao, Y.; Tian, Y.; Cui, Y.; Liu, W.; Ma, W.; Jiang, X. Small molecule-capped gold nanoparticles as potent antibacterial agents that target gram-negative bacteria. J. Am. Chem. Soc. 2010, 132, 12349–12356. [Google Scholar] [CrossRef]
  145. Cui, Y.; Zhao, Y.; Tian, Y.; Zhang, W.; Lü, X.; Jiang, X. The molecular mechanism of action of bactericidal gold nanoparticles on Escherichia coli. Biomaterials 2012, 33, 2327–2333. [Google Scholar] [CrossRef] [PubMed]
  146. Lemire, J.A.; Harrison, J.J.; Turner, R.J. Antimicrobial activity of metals: Mechanisms, molecular targets and applications. Nat. Rev. Microbiol. 2013, 11, 371–384. [Google Scholar] [CrossRef] [PubMed]
  147. Tarrat, N.; Benoit, M.; Giraud, M.; Ponchet, A.; Casanove, M.-J. The gold/ampicillin interface at the atomic scale. Nanoscale 2015, 7, 14515–14524. [Google Scholar] [CrossRef] [PubMed]
  148. Kim, D.; Kwon, S.J.; Wu, X.; Sauve, J.; Lee, I.; Nam, J.; Kim, J.; Dordick, J.S. Selective Killing of Pathogenic Bacteria by Antimicrobial Silver Nanoparticle-Cell Wall Binding Domain Conjugates. ACS Appl. Mater. Interfaces 2018, 10, 13317–13324. [Google Scholar] [CrossRef]
  149. Jijie, R.; Barras, A.; Teodorescu, F.; Boukherroub, R.; Szunerits, S. Advancements on the molecular design of nanoantibiotics: Current level of development and future challenges. Mol. Syst. Des. Eng. 2017, 2, 349–369. [Google Scholar] [CrossRef] [Green Version]
  150. Cheeseman, S.; Christofferson, A.J.; Kariuki, R.; Cozzolino, D.; Daeneke, T.; Crawford, R.J.; Truong, V.K.; Chapman, J.; Elbourne, A. Antimicrobial metal nanomaterials: From passive to stimuli-activated applications. Adv. Sci. 2020, 7, 1902913. [Google Scholar] [CrossRef] [Green Version]
  151. Hochvaldová, L.; Večeřová, R.; Kolář, M.; Prucek, R.; Kvítek, L.; Lapčík, L.; Panáček, A. Antibacterial nanomaterials: Upcoming hope to overcome antibiotic resistance crisis. Nanotechnol. Rev. 2022, 11, 1115–1142. [Google Scholar] [CrossRef]
  152. Gupta, A.; Mumtaz, S.; Li, C.-H.; Hussain, I.; Rotello, V.M. Combatting antibiotic-resistant bacteria using nanomaterials. Chem. Soc. Rev. 2019, 48, 415–427. [Google Scholar]
  153. Muthukrishnan, L.; Chellappa, M.; Nanda, A. Bio-engineering and cellular imaging of silver nanoparticles as weaponry against multidrug resistant human pathogens. J. Photochem. Photobiol. B Biol. 2019, 194, 119–127. [Google Scholar] [CrossRef]
  154. Wang, L.; Hu, C.; Shao, L. The antimicrobial activity of nanoparticles: Present situation and prospects for the future. Int. J. Nanomed. 2017, 12, 1227. [Google Scholar] [CrossRef] [Green Version]
  155. Slavin, Y.N.; Asnis, J.; Häfeli, U.O.; Bach, H. Metal nanoparticles: Understanding the mechanisms behind antibacterial activity. J. Nanobiotechnology 2017, 15, 65. [Google Scholar] [CrossRef]
  156. Wang, X.; Du, Y.; Fan, L.; Liu, H.; Hu, Y. Chitosan-metal complexes as antimicrobial agent: Synthesis, characterization and Structure-activity study. Polym. Bull. 2005, 55, 105–113. [Google Scholar] [CrossRef]
  157. Natan, M.; Banin, E. From nano to micro: Using nanotechnology to combat microorganisms and their multidrug resistance. FEMS Microbiol. Rev. 2017, 41, 302–322. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  158. Fenoglio, I.; Corazzari, I.; Francia, C.; Bodoardo, S.; Fubini, B. The oxidation of glutathione by cobalt/tungsten carbide contributes to hard metal-induced oxidative stress. Free. Radic. Res. 2008, 42, 437–745. [Google Scholar] [CrossRef] [PubMed]
  159. Quinteros, M.; Aristizábal, V.C.; Dalmasso, P.R.; Paraje, M.G.; Páez, P.L. Oxidative stress generation of silver nanoparticles in three bacterial genera and its relationship with the antimicrobial activity. Toxicol. Vitr. 2016, 36, 216–223. [Google Scholar] [CrossRef] [PubMed]
  160. Hailan, W.A.; Al-Anazi, K.M.; Farah, M.A.; Ali, M.A.; Al-Kawmani, A.A.; Abou-Tarboush, F.M. Reactive Oxygen Species-Mediated Cytotoxicity in Liver Carcinoma Cells Induced by Silver Nanoparticles Biosynthesized Using Schinus molle Extract. Nanomaterials 2022, 12, 161. [Google Scholar] [CrossRef]
  161. Banerjee, S.; Vishakha, K.; Das, S.; Sangma, P.D.; Mondal, S.; Ganguli, A. Oxidative stress, DNA, and membranes targets as modes of antibacterial and antibiofilm activity of facile synthesized biocompatible keratin-copper nanoparticles against multidrug resistant uro-pathogens. World J. Microbiol. Biotechnol. 2022, 38, 20. [Google Scholar] [CrossRef]
  162. Fahimmunisha, B.A.; Ishwarya, R.; AlSalhi, M.S.; Devanesan, S.; Govindarajan, M.; Vaseeharan, B. Green fabrication, characterization and antibacterial potential of zinc oxide nanoparticles using Aloe socotrina leaf extract: A novel drug delivery approach. J. Drug Deliv. Sci. Technol. 2020, 55, 101465. [Google Scholar] [CrossRef]
  163. Pathakoti, K.; Manubolu, M.; Hwang, H.M. Effect of Size and Crystalline Phase of TiO₂ Nanoparticles on Photocatalytic Inactivation of Escherichia coli. J. Nanosci. Nanotechnol. 2019, 19, 8172–8179. [Google Scholar] [CrossRef] [PubMed]
  164. Bardestani, A.; Ebrahimpour, S.; Esmaeili, A.; Esmaeili, A. Quercetin attenuates neurotoxicity induced by iron oxide nanoparticles. J. Nanobiotechnology 2021, 19, 327. [Google Scholar] [CrossRef]
  165. Chaithawiwat, K.; Vangnai, A.; McEvoy, J.M.; Pruess, B.; Krajangpan, S.; Khan, E. Role of oxidative stress in inactivation of Escherichia coli BW25113 by nanoscale zero-valent iron. Sci. Total Environ. 2016, 565, 857–862. [Google Scholar] [CrossRef]
  166. Ševců, A.; El-Temsah, Y.S.; Joner, E.J.; Černík, M. Oxidative stress induced in microorganisms by zero-valent iron nanoparticles. Microbes Environ. 2011, 26, 271–281. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  167. Shamaila, S.; Zafar, N.; Riaz, S.; Sharif, R.; Nazir, J.; Naseem, S. Gold nanoparticles: An efficient antimicrobial agent against enteric bacterial human pathogen. Nanomaterials 2016, 6, 71. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  168. Chatterjee, A.K.; Chakraborty, R.; Basu, T. Mechanism of antibacterial activity of copper nanoparticles. Nanotechnology 2014, 25, 135101. [Google Scholar] [CrossRef] [PubMed]
  169. Sutherland, I.W. The biofilm matrix--an immobilized but dynamic microbial environment. Trends Microbiol. 2001, 9, 222–227. [Google Scholar] [CrossRef] [PubMed]
  170. Hosnedlova, B.; Kabanov, D.; Kepinska, M.; VH, B.N.; Parikesit, A.A.; Fernandez, C.; Bjørklund, G.; Nguyen, H.V.; Farid, A.; Sochor, J.; et al. Effect of Biosynthesized Silver Nanoparticles on Bacterial Biofilm Changes in S. aureus and E. coli. Nanomaterials 2022, 12, 2183. [Google Scholar] [CrossRef]
  171. Brown, A.N.; Smith, K.; Samuels, T.A.; Lu, J.; Obare, S.O.; Scott, M.E. Nanoparticles functionalized with ampicillin destroy multiple-antibiotic-resistant isolates of Pseudomonas aeruginosa and Enterobacter aerogenes and methicillin-resistant Staphylococcus aureus. Appl. Environ. Microbiol. 2012, 78, 2768–2774. [Google Scholar] [CrossRef] [Green Version]
  172. Li, C.-H.; Chen, X.; Landis, R.F.; Geng, Y.; Makabenta, J.M.; Lemnios, W.; Gupta, A.; Rotello, V.M. Phytochemical-based nanocomposites for the treatment of bacterial biofilms. ACS Infect. Dis. 2019, 5, 1590–1596. [Google Scholar] [CrossRef]
  173. Abo-Shama, U.H.; El-Gendy, H.; Mousa, W.S.; Hamouda, R.A.; Yousuf, W.E.; Hetta, H.F.; Abdeen, E.E. Synergistic and antagonistic effects of metal nanoparticles in combination with antibiotics against some reference strains of pathogenic microorganisms. Infect. Drug Resist. 2020, 13, 351. [Google Scholar] [CrossRef] [Green Version]
  174. Bera, S.M.D. Drug Targeting and Stimuli Sensitive Drug Delivery Systems; William Andrew Publishing: Norwich, NY, USA, 2018; pp. 271–302. [Google Scholar]
  175. Li, P.; Li, J.; Wu, C.; Wu, Q.; Li, J. Synergistic antibacterial effects of β-lactam antibiotic combined with silver nanoparticles. Nanotechnology 2005, 16, 1912. [Google Scholar] [CrossRef]
  176. Chamundeeswari, M.; Sobhana, S.L.; Jacob, J.P.; Kumar, M.G.; Devi, M.P.; Sastry, T.P.; Mandal, A.B. Preparation, characterization and evaluation of a biopolymeric gold nanocomposite with antimicrobial activity. Biotechnol. Appl. Biochem. 2010, 55, 29–35. [Google Scholar] [CrossRef]
  177. Abdelghany, S.M.; Quinn, D.J.; Ingram, R.J.; Gilmore, B.F.; Donnelly, R.F.; Taggart, C.C.; Scott, C.J. Gentamicin-loaded nanoparticles show improved antimicrobial effects towards Pseudomonas aeruginosa infection. Int. J. Nanomed. 2012, 7, 4053. [Google Scholar]
  178. Hazime, N.; Belguesmia, Y.; Kempf, I.; Barras, A.; Drider, D.; Boukherroub, R. Enhancing Colistin Activity against Colistin-Resistant Escherichia coli through Combination with Alginate Nanoparticles and Small Molecules. Pharmaceuticals 2022, 15, 682. [Google Scholar] [CrossRef]
  179. Hada, A.M.; Potara, M.; Astilean, S.; Cordaro, A.; Neri, G.; Malanga, M.; Nostro, A.; Mazzaglia, A.; Scala, A.; Piperno, A. Linezolid nanoAntiobiotics and SERS-nanoTags based on polymeric cyclodextrin bimetallic core-shell nanoarchitectures. Carbohydr. Polym. 2022, 293, 119736. [Google Scholar] [CrossRef] [PubMed]
  180. Rumbaugh, K.P.; Sauer, K. Biofilm dispersion. Nat. Rev. Microbiol. 2020, 18, 571–586. [Google Scholar] [CrossRef] [PubMed]
  181. Michael, C.A.; Dominey-Howes, D.; Labbate, M. The antimicrobial resistance crisis: Causes, consequences, and management. Front. Public Health 2014, 2, 145. [Google Scholar] [CrossRef] [PubMed]
  182. Cassandra, W. The drug-resistant bacteria that pose the greatest health threats. Nature 2017, 543, 15. [Google Scholar]
  183. Huang, C.-M.; Chen, C.-H.; Pornpattananangkul, D.; Zhang, L.; Chan, M.; Hsieh, M.-F.; Zhang, L. Eradication of drug resistant Staphylococcus aureus by liposomal oleic acids. Biomaterials 2011, 32, 214–221. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  184. Sun, C.; Wang, X.; Dai, J.; Ju, Y. Metal and Metal Oxide Nanomaterials for Fighting Planktonic Bacteria and Biofilms: A Review Emphasizing on Mechanistic Aspects. Int. J. Mol. Sci. 2022, 23, 1348. [Google Scholar] [CrossRef]
  185. Liu, M.; Guo, L.; Fu, Y.; Huo, M.; Qi, Q.; Zhao, G. Bacterial protein acetylation and its role in cellular physiology and metabolic regulation. Biotechnol. Adv. 2021, 53, 107842. [Google Scholar] [CrossRef]
  186. Xu, Z.; Zhang, C.; Wang, X.; Liu, D. Release strategies of silver ions from materials for bacterial killing. ACS Appl. Bio. Mater. 2021, 4, 3985–3999. [Google Scholar] [CrossRef]
  187. Du, T.; Huang, B.; Cao, J.; Li, C.; Jiao, J.; Xiao, Z.; Wei, L.; Ma, J.; Du, X.; Wang, S. Ni Nanocrystals Supported on Graphene Oxide: Antibacterial Agents for Synergistic Treatment of Bacterial Infections. ACS Omega 2022, 7, 18339–18349. [Google Scholar] [CrossRef] [PubMed]
  188. Sondi, I.; Salopek-Sondi, B. Silver nanoparticles as antimicrobial agent: A case study on E. coli as a model for Gram-negative bacteria. J. Colloid Interface Sci. 2004, 275, 177–182. [Google Scholar] [CrossRef]
  189. Short, F.L.; Lee, V.; Mamun, R.; Malmberg, R.; Li, L.; Espinosa, M.I.; Abbu, K.-I.; Algie, J.; Callaghan, A.; Cenderawasih-Nere, P. Benzalkonium chloride antagonises aminoglycoside antibiotics and promotes evolution of resistance. EBioMedicine 2021, 73, 103653. [Google Scholar] [CrossRef] [PubMed]
  190. Zhang, X.; Zhang, Z.; Shu, Q.; Xu, C.; Zheng, Q.; Guo, Z.; Wang, C.; Hao, Z.; Liu, X.; Wang, G. Copper clusters: An effective antibacterial for eradicating multidrug-resistant bacterial infection in vitro and in vivo. Adv. Funct. Mater. 2021, 31, 2008720. [Google Scholar] [CrossRef]
  191. Emmanuel, R.; Palanisamy, S.; Chen, S.-M.; Chelladurai, K.; Padmavathy, S.; Saravanan, M.; Prakash, P.; Ali, M.A.; Al-Hemaid, F.M. Antimicrobial efficacy of green synthesized drug blended silver nanoparticles against dental caries and periodontal disease causing microorganisms. Mater. Sci. Eng. C 2015, 56, 374–379. [Google Scholar] [CrossRef] [PubMed]
  192. Sun, C.; Wang, W.; Sun, X.; Chu, W.; Yang, J.; Dai, J.; Ju, Y. An intrinsically thermogenic nanozyme for synergistic antibacterial therapy. Biomater. Sci. 2021, 9, 8323–8334. [Google Scholar] [CrossRef]
  193. Peng, B.; Su, Y.-b.; Li, H.; Han, Y.; Guo, C.; Tian, Y.-m.; Peng, X.-x. Exogenous alanine and/or glucose plus kanamycin kills antibiotic-resistant bacteria. Cell Metab. 2015, 21, 249–262. [Google Scholar] [CrossRef] [Green Version]
  194. Marambio-Jones, C.; Hoek, E. A review of the antibacterial effects of silver nanomaterials and potential implications for human health and the environment. J. Nanoparticle Res. 2010, 12, 1531–1551. [Google Scholar] [CrossRef]
  195. Rizzello, L.; Pompa, P.P. Nanosilver-based antibacterial drugs and devices: Mechanisms, methodological drawbacks, and guidelines. Chem. Soc. Rev. 2014, 43, 1501–1518. [Google Scholar] [CrossRef]
  196. Eng, S.-K.; Pusparajah, P.; Ab Mutalib, N.-S.; Ser, H.-L.; Chan, K.-G.; Lee, L.-H. Salmonella: A review on pathogenesis, epidemiology and antibiotic resistance. Front. Life Sci. 2015, 8, 284–293. [Google Scholar] [CrossRef] [Green Version]
  197. Hetta, H.F.; Meshaal, A.K.; Algammal, A.M.; Yahia, R.; Makharita, R.R.; Marraiki, N.; Shah, M.A.; Hassan, H.-A.M.; Batiha, G.E.-S. In-vitro antimicrobial activity of essential oils and spices powder of some medicinal plants against bacillus species isolated from raw and processed meat. Infect. Drug Resist. 2020, 13, 4367. [Google Scholar] [CrossRef] [PubMed]
  198. Ibarra, J.A.; Steele-Mortimer, O. Salmonella–the ultimate insider. Salmonella virulence factors that modulate intracellular survival. Cell. Microbiol. 2009, 11, 1579–1586. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  199. Kamaruzzaman, N.F.; Kendall, S.; Good, L. Targeting the hard to reach: Challenges and novel strategies in the treatment of intracellular bacterial infections. Br. J. Pharmacol. 2017, 174, 2225–2236. [Google Scholar] [CrossRef] [Green Version]
  200. Russell, D.G. Mycobacterium tuberculosis: Here today, and here tomorrow. Nat. Rev. Mol. Cell Biol. 2001, 2, 569–578. [Google Scholar] [CrossRef]
  201. El-Masry, E.A.; Taher, I.; Hetta, H.F.; Eldahdouh, S.S. Pulmonary tuberculosis susceptibility and association with Toll-Like receptor 2 Arg753Gln polymorphism. J. Infect. Dev. Ctries. 2022, 16, 125–133. [Google Scholar] [CrossRef]
  202. Algammal, A.M.; Hashem, H.R.; Al-Otaibi, A.S.; Alfifi, K.J.; El-Dawody, E.M.; Mahrous, E.; Hetta, H.F.; El-Kholy, A.W.; Ramadan, H.; El-Tarabili, R.M. Emerging MDR-Mycobacterium avium subsp. avium in house-reared domestic birds as the first report in Egypt. BMC Microbiol. 2021, 21, 237. [Google Scholar] [CrossRef]
  203. Dar, H.A.; Ismail, S.; Waheed, Y.; Ahmad, S.; Jamil, Z.; Aziz, H.; Hetta, H.F.; Muhammad, K. Designing a multi-epitope vaccine against Mycobacteroides abscessus by pangenome-reverse vaccinology. Sci. Rep. 2021, 11, 11197. [Google Scholar] [CrossRef]
  204. Ellis, T.; Chiappi, M.; Garcia-Trenco, A.; Al-Ejji, M.; Sarkar, S.; Georgiou, T.K.; Shaffer, M.S.; Tetley, T.D.; Schwander, S.; Ryan, M.P. Multimetallic microparticles increase the potency of rifampicin against intracellular Mycobacterium tuberculosis. ACS Nano 2018, 12, 5228–5240. [Google Scholar] [CrossRef]
  205. Jiang, H.; Li, X.; Xing, Z.; Niu, Q.; Xu, J. Intracellular Activity of Poly (DL-lactide-co-glycolide) Nanoparticles Encapsulated with Prothionamide, Pyrazinamide, Levofloxacin, Linezolid or Ethambutol on Multidrug-Resistant Mycobacterium Tuberculosis. Curr. Drug Deliv. 2022. online ahead of print. [Google Scholar] [CrossRef]
  206. Xie, X.; Du, X.; Li, K.; Chen, Y.; Guan, Y.; Zhao, X.; Niu, G.; Luan, Y.; Zhang, D.; Sun, C.; et al. Construction of engineered corpus cavernosum with primary mesenchymal stem cells in vitro. Sci. Rep. 2017, 7, 18053. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  207. Menina, S.; Eisenbeis, J.; Kamal, M.A.M.; Koch, M.; Bischoff, M.; Gordon, S.; Loretz, B.; Lehr, C.M. Bioinspired liposomes for oral delivery of colistin to combat intracellular infections by Salmonella enterica. Adv. Healthc. Mater. 2019, 8, 1900564. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  208. Mu, H.; Tang, J.; Liu, Q.; Sun, C.; Wang, T.; Duan, J. Potent antibacterial nanoparticles against biofilm and intracellular bacteria. Sci. Rep. 2016, 6, 18877. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  209. Li, Y.; Wang, J.; Li, B.; Geng, M.; Wang, Y.; Zhao, J.; Jin, B.; Li, Y. Response of extracellular polymeric substances and microbial community structures on resistance genes expression in wastewater treatment containing copper oxide nanoparticles and humic acid. Bioresour. Technol. 2021, 340, 125741. [Google Scholar] [CrossRef]
  210. Costerton, J.W.; Stewart, P.S.; Greenberg, E.P. Bacterial biofilms: A common cause of persistent infections. Science 1999, 284, 1318–1322. [Google Scholar] [CrossRef] [Green Version]
  211. Geesey, G.; Richardson, W.; Yeomans, H.; Irvin, R.; Costerton, J. Microscopic examination of natural sessile bacterial populations from an alpine stream. Can. J. Microbiol. 1977, 23, 1733–1736. [Google Scholar] [CrossRef]
  212. Flemming, H.-C.; Wingender, J.; Szewzyk, U.; Steinberg, P.; Rice, S.A.; Kjelleberg, S. Biofilms: An emergent form of bacterial life. Nat. Rev. Microbiol. 2016, 14, 563–575. [Google Scholar] [CrossRef]
  213. Arnaouteli, S.; Bamford, N.C.; Stanley-Wall, N.R.; Kovács, Á.T. Bacillus subtilis biofilm formation and social interactions. Nat. Rev. Microbiol. 2021, 19, 600–614. [Google Scholar] [CrossRef]
  214. Flemming, H.-C.; Wingender, J. The biofilm matrix. Nat. Rev. Microbiol. 2010, 8, 623–633. [Google Scholar] [CrossRef]
  215. Patel, R. Biofilms and antimicrobial resistance. Clin. Orthop. Relat. Res. 2005, 437, 41–47. [Google Scholar] [CrossRef]
  216. Van Acker, H.; Van Dijck, P.; Coenye, T. Molecular mechanisms of antimicrobial tolerance and resistance in bacterial and fungal biofilms. Trends Microbiol. 2014, 22, 326–333. [Google Scholar] [CrossRef]
  217. Sauer, K.; Stoodley, P.; Goeres, D.M.; Hall-Stoodley, L.; Burmølle, M.; Stewart, P.S.; Bjarnsholt, T. The biofilm life cycle: Expanding the conceptual model of biofilm formation. Nat. Rev. Microbiol. 2022, 20, 608–620. [Google Scholar] [CrossRef] [PubMed]
  218. Ciofu, O.; Moser, C.; Jensen, P.; Høiby, N. Tolerance and resistance of microbial biofilms. Nat. Rev. Microbiol. 2022, 20, 621–635. [Google Scholar] [CrossRef] [PubMed]
  219. Morales-Ubaldo, A.L.; Rivero-Perez, N.; Avila-Ramos, F.; Aquino-Torres, E.; Prieto-Méndez, J.; Hetta, H.F.; El-Saber Batiha, G.; Zaragoza-Bastida, A. Bactericidal activity of Larrea tridentata hydroalcoholic extract against phytopathogenic bacteria. Agronomy 2021, 11, 957. [Google Scholar] [CrossRef]
  220. Wang, Y.; Bian, Z.; Wang, Y. Biofilm formation and inhibition mediated by bacterial quorum sensing. Appl. Microbiol. Biotechnol. 2022, 106, 6365–6381. [Google Scholar] [CrossRef] [PubMed]
  221. Fulaz, S.; Vitale, S.; Quinn, L.; Casey, E. Nanoparticle–biofilm interactions: The role of the EPS matrix. Trends Microbiol. 2019, 27, 915–926. [Google Scholar] [CrossRef]
  222. Ikuma, K.; Decho, A.W.; Lau, B.L. When nanoparticles meet biofilms—Interactions guiding the environmental fate and accumulation of nanoparticles. Front. Microbiol. 2015, 6, 591. [Google Scholar] [CrossRef]
  223. Birk, S.E.; Boisen, A.; Nielsen, L.H. Polymeric nano- and microparticulate drug delivery systems for treatment of biofilms. Adv. Drug Deliv. Rev. 2021, 174, 30–52. [Google Scholar] [CrossRef]
  224. Banerjee, S.; Vishakha, K.; Das, S.; Dutta, M.; Mukherjee, D.; Mondal, J.; Mondal, S.; Ganguli, A. Antibacterial, anti-biofilm activity and mechanism of action of pancreatin doped zinc oxide nanoparticles against methicillin resistant Staphylococcus aureus. Colloids Surf. B Biointerfaces 2020, 190, 110921. [Google Scholar] [CrossRef]
  225. Thomas, N.; Thorn, C.; Richter, K.; Thierry, B.; Prestidge, C. Efficacy of Poly-Lactic-Co-Glycolic Acid Micro- and Nanoparticles of Ciprofloxacin Against Bacterial Biofilms. J. Pharm. Sci. 2016, 105, 3115–3122. [Google Scholar] [CrossRef]
  226. Zazo, H.; Colino, C.I.; Lanao, J.M. Current applications of nanoparticles in infectious diseases. J. Control. Release 2016, 224, 86–102. [Google Scholar] [CrossRef] [PubMed]
  227. Huh, A.J.; Kwon, Y.J. “Nanoantibiotics”: A new paradigm for treating infectious diseases using nanomaterials in the antibiotics resistant era. J. Control. Release 2011, 156, 128–145. [Google Scholar] [CrossRef] [PubMed]
  228. Baptista, P.V.; McCusker, M.P.; Carvalho, A.; Ferreira, D.A.; Mohan, N.M.; Martins, M.; Fernandes, A.R. Nano-strategies to fight multidrug resistant bacteria—“A Battle of the Titans”. Front. Microbiol. 2018, 9, 1441. [Google Scholar] [CrossRef] [Green Version]
  229. Sandhiya, S.; Dkhar, S.A.; Surendiran, A. Emerging trends of nanomedicine--an overview. Fundam. Clin. Pharmacol. 2009, 23, 263–269. [Google Scholar] [CrossRef] [PubMed]
  230. El-Ansary, A.; Al-Daihan, S. On the Toxicity of Therapeutically Used Nanoparticles: An Overview. J. Toxicol. 2009, 2009, 754810. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  231. Hagens, W.I.; Oomen, A.G.; de Jong, W.H.; Cassee, F.R.; Sips, A.J.A.M. What do we (need to) know about the kinetic properties of nanoparticles in the body? Regul. Toxicol. Pharmacol. 2007, 49, 217–229. [Google Scholar] [CrossRef]
  232. De Jong, W.H.; Borm, P.J. Drug delivery and nanoparticles:applications and hazards. Int. J. Nanomed. 2008, 3, 133–149. [Google Scholar] [CrossRef] [Green Version]
  233. Miyazaki, T.; Chen, S.; Florinas, S.; Igarashi, K.; Matsumoto, Y.; Yamasoba, T.; Xu, Z.-Q.; Wu, H.; Gao, C.; Kataoka, K. A Hoechst Reporter Enables Visualization of Drug Engagement In Vitro and In Vivo: Toward Safe and Effective Nanodrug Delivery. ACS Nano 2022, 16, 12290–12304. [Google Scholar] [CrossRef]
  234. Duncan, R.; Gaspar, R. Nanomedicine(s) under the microscope. Mol. Pharm. 2011, 8, 2101–2141. [Google Scholar] [CrossRef]
Biomedicines 11 00413 g001 550
Figure 1. Loading NPs with conventional antibiotics. NPs act as a delivery system to transfer Ab to its target in resistant microorganism. This provides dual mechanisms to combat MDR organism through the effect of Ab and the effect of NPs itself with net result potentiation of bacterial cell death. Abs exert their bactericide effect through disruption of bacterial cell wall or cell membrane, destabilization of ribosomes and inhibition of protein synthesis or inhibition of nucleic acid synthesis. NPs may act through more than one mechanism; disruption of cell wall and cell membrane, mitochondrial damage, enzyme damage, protein damage, efflux pump damage, inhibition of electron transport chain and production of ROS that generate oxidative stress and lead to damage of vital cellular macromolecules.
Figure 1. Loading NPs with conventional antibiotics. NPs act as a delivery system to transfer Ab to its target in resistant microorganism. This provides dual mechanisms to combat MDR organism through the effect of Ab and the effect of NPs itself with net result potentiation of bacterial cell death. Abs exert their bactericide effect through disruption of bacterial cell wall or cell membrane, destabilization of ribosomes and inhibition of protein synthesis or inhibition of nucleic acid synthesis. NPs may act through more than one mechanism; disruption of cell wall and cell membrane, mitochondrial damage, enzyme damage, protein damage, efflux pump damage, inhibition of electron transport chain and production of ROS that generate oxidative stress and lead to damage of vital cellular macromolecules.
Biomedicines 11 00413 g001
Biomedicines 11 00413 g002 550
Figure 2. Mechanisms of development of antibiotic resistance. It develops through different mechanisms: (1) breakdown of drugs through production of inactivating enzyme, (2) decrease in antibiotic uptake, (3) alteration of common metabolic pathway, (4) extrusion of drug outside the cell by efflux pump, (5) change and alteration in antibiotic target, (6) presence of plasmid carrying multiple resistance genes, (7) sharing resistance gene between different bacteria, (8) formation of protective extracellular polymeric matrix.
Figure 2. Mechanisms of development of antibiotic resistance. It develops through different mechanisms: (1) breakdown of drugs through production of inactivating enzyme, (2) decrease in antibiotic uptake, (3) alteration of common metabolic pathway, (4) extrusion of drug outside the cell by efflux pump, (5) change and alteration in antibiotic target, (6) presence of plasmid carrying multiple resistance genes, (7) sharing resistance gene between different bacteria, (8) formation of protective extracellular polymeric matrix.
Biomedicines 11 00413 g002
Biomedicines 11 00413 g003 550
Figure 3. Risk factors related to MDR. MDR increase the risk of mortality rate, decrease in medication efficacy, prolong the period of illness, rapidly develop in immunocompromised patients, are not affected by most antimicrobials and need more expensive alternatives.
Figure 3. Risk factors related to MDR. MDR increase the risk of mortality rate, decrease in medication efficacy, prolong the period of illness, rapidly develop in immunocompromised patients, are not affected by most antimicrobials and need more expensive alternatives.
Biomedicines 11 00413 g003
Biomedicines 11 00413 g004 550
Figure 4. Mechanisms of action of NPs. They act through destruction of bacterial cell wall and cell membrane, overproduction of reactive oxygen species (ROS) that produce oxidative stress and damage vital intracellular macromolecules, as well as inflict protein damage, enzyme damage, mitochondrial damage, DNA damage, alteration in membrane permeability, prevent extrusion of drug through damage of efflux pump, inhibition of electron transport chain and prevent and disrupt biofilm.
Figure 4. Mechanisms of action of NPs. They act through destruction of bacterial cell wall and cell membrane, overproduction of reactive oxygen species (ROS) that produce oxidative stress and damage vital intracellular macromolecules, as well as inflict protein damage, enzyme damage, mitochondrial damage, DNA damage, alteration in membrane permeability, prevent extrusion of drug through damage of efflux pump, inhibition of electron transport chain and prevent and disrupt biofilm.
Biomedicines 11 00413 g004
Biomedicines 11 00413 g005 550
Figure 5. Synergistic activity of nanoparticles loaded with antibiotics. Combined nanoantibiotics (nAbs) exert dual antibacterial action through the effect of nanoparticles and antibiotics. Antibiotics can exert rapid and potent action through targeted delivery by NPs and exert their bactericidal effect through disruption of bacterial cell wall or cell membrane, destabilization of ribosomes and inhibition of protein synthesis or inhibition of nucleic acid synthesis. In addition, NPs can cause damage to bacterial cell wall, cell membrane, proteins, DNA, enzymes, mitochondria, efflux pump and inhibit electron transport and release reactive oxygen species (ROS) that cause damage to vital cellular macromolecules.
Figure 5. Synergistic activity of nanoparticles loaded with antibiotics. Combined nanoantibiotics (nAbs) exert dual antibacterial action through the effect of nanoparticles and antibiotics. Antibiotics can exert rapid and potent action through targeted delivery by NPs and exert their bactericidal effect through disruption of bacterial cell wall or cell membrane, destabilization of ribosomes and inhibition of protein synthesis or inhibition of nucleic acid synthesis. In addition, NPs can cause damage to bacterial cell wall, cell membrane, proteins, DNA, enzymes, mitochondria, efflux pump and inhibit electron transport and release reactive oxygen species (ROS) that cause damage to vital cellular macromolecules.
Biomedicines 11 00413 g005
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Hetta, H.F.; Ramadan, Y.N.; Al-Harbi, A.I.; A. Ahmed, E.; Battah, B.; Abd Ellah, N.H.; Zanetti, S.; Donadu, M.G. Nanotechnology as a Promising Approach to Combat Multidrug Resistant Bacteria: A Comprehensive Review and Future Perspectives. Biomedicines 2023, 11, 413. https://doi.org/10.3390/biomedicines11020413

AMA Style

Hetta HF, Ramadan YN, Al-Harbi AI, A. Ahmed E, Battah B, Abd Ellah NH, Zanetti S, Donadu MG. Nanotechnology as a Promising Approach to Combat Multidrug Resistant Bacteria: A Comprehensive Review and Future Perspectives. Biomedicines. 2023; 11(2):413. https://doi.org/10.3390/biomedicines11020413

Chicago/Turabian Style

Hetta, Helal F., Yasmin N. Ramadan, Alhanouf I. Al-Harbi, Esraa A. Ahmed, Basem Battah, Noura H. Abd Ellah, Stefania Zanetti, and Matthew Gavino Donadu. 2023. "Nanotechnology as a Promising Approach to Combat Multidrug Resistant Bacteria: A Comprehensive Review and Future Perspectives" Biomedicines 11, no. 2: 413. https://doi.org/10.3390/biomedicines11020413

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop