Research

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22 pages, 1907 KiB

Open AccessArticle

Dibasic Derivatives of Phenylcarbamic Acid as Prospective Antibacterial Agents Interacting with Cytoplasmic Membrane

by Šárka Pospíšilová, Ivan Malík, Kristyna Bezouskova, Tereza Kauerova, Peter Kollar, Jozef Csöllei, Michal Oravec, Alois Cizek and Josef Jampilek

Antibiotics 2020, 9(2), 64; https://doi.org/10.3390/antibiotics9020064 - 06 Feb 2020

Cited by 6 | Viewed by 2782

Abstract

1-[2-[({[2-/3-(Alkoxy)phenyl]amino}carbonyl)oxy]-3-(dipropylammonio)propyl]pyrrolidinium/azepan- ium oxalates or dichlorides (alkoxy = butoxy to heptyloxy) were recently described as very promising antimycobacterial agents. These compounds were tested in vitro against Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212 (reference and control strains), three methicillin-resistant isolates of S. aureus [...] Read more.

1-[2-[({[2-/3-(Alkoxy)phenyl]amino}carbonyl)oxy]-3-(dipropylammonio)propyl]pyrrolidinium/azepan- ium oxalates or dichlorides (alkoxy = butoxy to heptyloxy) were recently described as very promising antimycobacterial agents. These compounds were tested in vitro against Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212 (reference and control strains), three methicillin-resistant isolates of S. aureus, and three isolates of vancomycin-resistant E. faecalis. 1-[3-(Dipropylammonio)-2-({[3-(pentyloxy-/hexyloxy-/heptyloxy)phenyl]carbamoyl}oxy)propyl]pyrrolidinium dichlorides showed high activity against staphylococci and enterococci comparable with or higher than that of used controls (clinically used antibiotics and antiseptics). The screening of the cytotoxicity of the compounds as well as the used controls was performed using human monocytic leukemia cells. IC₅₀ values of the most effective compounds ranged from ca. 3.5 to 6.3 µM, thus, it can be stated that the antimicrobial effect is closely connected with their cytotoxicity. The antibacterial activity is based on the surface activity of the compounds that are influenced by the length of their alkoxy side chain, the size of the azacyclic system, and hydro-lipophilic properties, as proven by in vitro experiments and chemometric principal component analyses. Synergistic studies showed the increased activity of oxacillin, gentamicin, and vancomycin, which could be explained by the direct activity of the compounds against the bacterial cell wall. All these compounds demonstrate excellent antibiofilm activity, when they inhibit and disrupt the biofilm of S. aureus in concentrations close to minimum inhibitory concentrations against planktonic cells. Expected interactions of the compounds with the cytoplasmic membrane are proven by in vitro crystal violet uptake assays. Full article

(This article belongs to the Special Issue Novel Strategies against Pathogenic Bacteria)

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15 pages, 5691 KiB

Open AccessArticle

Gut Bacteria of Water Monitor Lizard (Varanus salvator) Are a Potential Source of Antibacterial Compound(s)

by Noor Akbar, Ruqaiyyah Siddiqui, K Sagathevan, Mazhar Iqbal and Naveed Ahmed Khan

Antibiotics 2019, 8(4), 164; https://doi.org/10.3390/antibiotics8040164 - 24 Sep 2019

Cited by 21 | Viewed by 5596

Abstract

For the past few decades, there has been limited progress in the development of novel antibacterials. Previously, we postulated that the gut microbiota of animals residing in polluted environments are a forthcoming supply of antibacterials. Among various species, the water monitor lizard is [...] Read more.

For the past few decades, there has been limited progress in the development of novel antibacterials. Previously, we postulated that the gut microbiota of animals residing in polluted environments are a forthcoming supply of antibacterials. Among various species, the water monitor lizard is an interesting species that feeds on organic waste and the carcass of wild animals. Gut microbiota of the water monitor lizard were sequestered, identified and cultivated in RPMI-1640 to produce conditioned medium (CM). Next, the antimicrobial properties of CM were evaluated versus a selection of Gram-negative (Escherichia coli K1, Serratia marcescens, Pseudomonas aeruginosa, Salmonella enterica and Klebsiella pneumoniae) and Gram-positive bacteria (Streptococcus pyogenes, methicillin-resistant Staphylococcus aureus, and Bacillus cereus). CM were partially characterized by heat inactivation at 95°C for 10 min and tested against P. aeruginosa and S. pyogenes. CM were also tested against immortalized human keratinocytes (HaCaT) cells lines. The results demonstrated that gut microbiota isolated from water monitor lizard produced molecules with remarkable bactericidal activities. To determine the identity of the active molecules, CM were subjected to Liquid Chromatography-Mass Spectrometry. Several molecules were identified belonging to the classes of flavonoids, terpenoids, alkaloids, polyhydroxy alkaloids, polyacetylenes, bisphenols, amides, oxylipin and pyrazine derivatives with known broad-spectrum antimicrobial, anti-tumour, anti-oxidant, anti-inflammatory, and analgesic attributes. Furthermore, the detailed analysis of these molecules could lead us to develop effective therapeutic antibacterials. Full article

(This article belongs to the Special Issue Novel Strategies against Pathogenic Bacteria)

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19 pages, 1819 KiB

Open AccessArticle

Development of a High Throughput Screen for the Identification of Inhibitors of Peptidoglycan O-Acetyltransferases, New Potential Antibacterial Targets

by Ashley S. Brott, Carys S. Jones and Anthony J. Clarke

Antibiotics 2019, 8(2), 65; https://doi.org/10.3390/antibiotics8020065 - 27 May 2019

Cited by 7 | Viewed by 4471

Abstract

The O-acetylation of peptidoglycan occurs in many Gram-negative and most Gram-positive pathogens and this modification to the essential wall polymer controls the lytic activity of the autolysins, particularly the lytic transglycosylases, and inhibits that of the lysozymes of innate immunity systems. As [...] Read more.

The O-acetylation of peptidoglycan occurs in many Gram-negative and most Gram-positive pathogens and this modification to the essential wall polymer controls the lytic activity of the autolysins, particularly the lytic transglycosylases, and inhibits that of the lysozymes of innate immunity systems. As such, the peptidoglycan O-acetyltransferases PatA/B and OatA are recognized as virulence factors. In this study, we present the high throughput screening of small compound libraries to identify the first known inhibitors of these enzymes. The fluorometric screening assay developed involved monitoring the respective O-acetyltransferases as esterases using 4-methylumbelliferylacetate as substrate. Pilot screens of 3921 compounds validated the usefulness of the HTS protocol. A number of potential inhibitors were identified amongst a total of 145,000 low molecular-weight compounds, some of which were common to both enzymes, while others were unique to each. After eliminating a number of false positives in secondary screens, dose response curves confirmed the apparent specificity of a benzothiazolyl-pyrazolo-pyridine as an inhibitor of Neisseria gonorrhoeae PatB, and several coumarin-based compounds as inhibitors of both this PatB and OatA from Staphylococcus aureus. The benzothiazolyl-pyrazolo-pyridine was determined to be a non-competitive inhibitor of PatB with a K_i of 126 µM. At 177 µg/mL and close to its solubility limit, this compound caused a 90% reduction in growth of N. gonorrhoeae, while growth of Escherichia coli, a bacterium that lacks PatB and, hence, does not produce O-acetylated peptidoglycan, was unaffected. These data provide preliminary proof of concept that peptidoglycan O-acetyltransferases would serve as useful antibacterial targets. Full article

(This article belongs to the Special Issue Novel Strategies against Pathogenic Bacteria)

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Review

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25 pages, 779 KiB

Open AccessReview

Looking beyond Typical Treatments for Atypical Mycobacteria

by Clara M. Bento, Maria Salomé Gomes and Tânia Silva

Antibiotics 2020, 9(1), 18; https://doi.org/10.3390/antibiotics9010018 - 03 Jan 2020

Cited by 31 | Viewed by 8366

Abstract

The genus Mycobacterium comprises not only the deadliest of bacterial pathogens, Mycobacterium tuberculosis, but several other pathogenic species, including M. avium and M. abscessus. The incidence of infections caused by atypical or nontuberculous mycobacteria (NTM) has been steadily increasing, and is [...] Read more.

The genus Mycobacterium comprises not only the deadliest of bacterial pathogens, Mycobacterium tuberculosis, but several other pathogenic species, including M. avium and M. abscessus. The incidence of infections caused by atypical or nontuberculous mycobacteria (NTM) has been steadily increasing, and is associated with a panoply of diseases, including pulmonary, soft-tissue, or disseminated infections. The treatment for NTM disease is particularly challenging, due to its long duration, to variability in bacterial susceptibility profiles, and to the lack of evidence-based guidelines. Treatment usually consists of a combination of at least three drugs taken from months to years, often leading to severe secondary effects and a high chance of relapse. Therefore, new treatment approaches are clearly needed. In this review, we identify the main limitations of current treatments and discuss different alternatives that have been put forward in recent years, with an emphasis on less conventional therapeutics, such as antimicrobial peptides, bacteriophages, iron chelators, or host-directed therapies. We also review new forms of the use of old drugs, including the repurposing of non-antibacterial molecules and the incorporation of antimicrobials into ionic liquids. We aim to stimulate advancements in testing these therapies in relevant models, in order to provide clinicians and patients with useful new tools with which to treat these devastating diseases. Full article

(This article belongs to the Special Issue Novel Strategies against Pathogenic Bacteria)

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12 pages, 410 KiB

Open AccessReview

The Use of Nanomedicine for Targeted Therapy against Bacterial Infections

by Abdulkader Masri, Ayaz Anwar, Naveed Ahmed Khan and Ruqaiyyah Siddiqui

Antibiotics 2019, 8(4), 260; https://doi.org/10.3390/antibiotics8040260 - 11 Dec 2019

Cited by 37 | Viewed by 5148

Abstract

The emergence of drug resistance combined with limited success in the discovery of newer and effective antimicrobial chemotherapeutics poses a significant challenge to human and animal health. Nanoparticles may be an approach for effective drug development and delivery against infections caused by multi-drug [...] Read more.

The emergence of drug resistance combined with limited success in the discovery of newer and effective antimicrobial chemotherapeutics poses a significant challenge to human and animal health. Nanoparticles may be an approach for effective drug development and delivery against infections caused by multi-drug resistant bacteria. Here we discuss nanoparticles therapeutics and nano-drug delivery against bacterial infections. The therapeutic efficacy of numerous kinds of nanoparticles including nanoantibiotics conjugates, small molecules capped nanoparticles, polymers stabilized nanoparticles, and biomolecules functionalized nanoparticles has been discussed. Moreover, nanoparticles-based drug delivery systems against bacterial infections have been described. Furthermore, the fundamental limitation of biocompatibility and biosafety of nanoparticles is also conferred. Finally, we propose potential future strategies of nanomaterials as antibacterials. Full article

(This article belongs to the Special Issue Novel Strategies against Pathogenic Bacteria)

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16 pages, 937 KiB

Open AccessReview

Dissecting the Antimicrobial Composition of Honey

by Victoria C. Nolan, James Harrison and Jonathan A. G. Cox

Antibiotics 2019, 8(4), 251; https://doi.org/10.3390/antibiotics8040251 - 05 Dec 2019

Cited by 105 | Viewed by 19236

Abstract

Honey is a complex sweet food stuff with well-established antimicrobial and antioxidant properties. It has been used for millennia in a variety of applications, but the most noteworthy include the treatment of surface wounds, burns and inflammation. A variety of substances in honey [...] Read more.

Honey is a complex sweet food stuff with well-established antimicrobial and antioxidant properties. It has been used for millennia in a variety of applications, but the most noteworthy include the treatment of surface wounds, burns and inflammation. A variety of substances in honey have been suggested as the key component to its antimicrobial potential; polyphenolic compounds, hydrogen peroxide, methylglyoxal and bee-defensin 1. These components vary greatly across honey samples due to botanical origin, geographical location and secretions from the bee. The use of medical grade honey in the treatment of surface wounds and burns has been seen to improve the healing process, reduce healing time, reduce scarring and prevent microbial contamination. Therefore, if medical grade honeys were to be included in clinical treatment, it would reduce the demand for antibiotic usage. In this review, we outline the constituents of honey and how they affect antibiotic potential in a clinical setting. By identifying the key components, we facilitate the development of an optimally antimicrobial honey by either synthetic or semisynthetic production methods. Full article

(This article belongs to the Special Issue Novel Strategies against Pathogenic Bacteria)

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12 pages, 323 KiB

Open AccessReview

Host-Targeted Therapeutics against Multidrug Resistant Intracellular Staphylococcus aureus

by Natalia Bravo-Santano, Volker Behrends and Michal Letek

Antibiotics 2019, 8(4), 241; https://doi.org/10.3390/antibiotics8040241 - 28 Nov 2019

Cited by 8 | Viewed by 3992

Abstract

Staphylococcus aureus is a facultative intracellular pathogen that invades and replicates within many types of human cells. S. aureus has shown to rapidly overcome traditional antibiotherapy by developing multidrug resistance. Furthermore, intracellular S. aureus is protected from the last-resort antibiotics—vancomycin, daptomycin, and linezolid—as [...] Read more.

Staphylococcus aureus is a facultative intracellular pathogen that invades and replicates within many types of human cells. S. aureus has shown to rapidly overcome traditional antibiotherapy by developing multidrug resistance. Furthermore, intracellular S. aureus is protected from the last-resort antibiotics—vancomycin, daptomycin, and linezolid—as they are unable to achieve plasma concentrations sufficient for intracellular killing. Therefore, there is an urgent need to develop novel anti-infective therapies against S. aureus infections. Here, we review the current state of the field and highlight the exploitation of host-directed approaches as a promising strategy going forward. Full article

(This article belongs to the Special Issue Novel Strategies against Pathogenic Bacteria)

15 pages, 954 KiB

Open AccessReview

Harnessing the Potential of Killers and Altruists within the Microbial Community: A Possible Alternative to Antibiotic Therapy?

by Larisa N. Ikryannikova, Leonid K. Kurbatov, Surinder M. Soond and Andrey A. Zamyatnin, Jr.

Antibiotics 2019, 8(4), 230; https://doi.org/10.3390/antibiotics8040230 - 21 Nov 2019

Cited by 3 | Viewed by 4823

Abstract

In the context of a post-antibiotic era, the phenomenon of microbial allolysis, which is defined as the partial killing of bacterial population induced by other cells of the same species, may take on greater significance. This phenomenon was revealed in some bacterial species [...] Read more.

In the context of a post-antibiotic era, the phenomenon of microbial allolysis, which is defined as the partial killing of bacterial population induced by other cells of the same species, may take on greater significance. This phenomenon was revealed in some bacterial species such as Streptococcus pneumoniae and Bacillus subtilis, and has been suspected to occur in some other species or genera, such as enterococci. The mechanisms of this phenomenon, as well as its role in the life of microbial populations still form part of ongoing research. Herein, we describe recent developments in allolysis in the context of its practical benefits as a form of cell death that may give rise to developing new strategies for manipulating the life and death of bacterial communities. We highlight how such findings may be viewed with importance and potential within the fields of medicine, biotechnology, and pharmacology. Full article

(This article belongs to the Special Issue Novel Strategies against Pathogenic Bacteria)

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