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Review

Antibiotic Alternatives: Multifunctional Ultra-Small Metal Nanoclusters for Bacterial Infectious Therapy Application

by
Yuxian Wang
1,
Meng Gu
2,
Jiangyang Cheng
1,
Yusong Wan
1,
Liying Zhu
3,
Zhen Gao
2 and
Ling Jiang
4,*
1
College of Food Science and Light Industry, Nanjing Tech University, Nanjing 211816, China
2
College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 211816, China
3
School of Chemistry and Molecular Engineering, Nanjing Tech University, Nanjing 211816, China
4
State Key Laboratory of Materials-Oriented Chemical Engineering, College of Food Science and Light Industry, Nanjing Tech University, Nanjing 211816, China
*
Author to whom correspondence should be addressed.
Molecules 2024, 29(13), 3117; https://doi.org/10.3390/molecules29133117
Submission received: 4 June 2024 / Revised: 26 June 2024 / Accepted: 28 June 2024 / Published: 30 June 2024
(This article belongs to the Special Issue Advances in Nanomaterials for Biomedical Applications)
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Abstract

:
The prevalence of major bacterial infections has emerged as a significant menace to human health and life. Conventional treatment methods primarily rely on antibiotic therapy, but the overuse of these drugs has led to a decline in their efficacy. Moreover, bacteria have developed resistance towards antibiotics, giving rise to the emergence of superbugs. Consequently, there is an urgent need for novel antibacterial agents or alternative strategies to combat bacterial infections. Nanoantibiotics encompass a class of nano-antibacterial materials that possess inherent antimicrobial activity or can serve as carriers to enhance drug delivery efficiency and safety. In recent years, metal nanoclusters (M NCs) have gained prominence in the field of nanoantibiotics due to their ultra-small size (less than 3 nm) and distinctive electronic and optical properties, as well as their biosafety features. In this review, we discuss the recent progress of M NCs as a new generation of antibacterial agents. First, the main synthesis methods and characteristics of M NCs are presented. Then, we focus on reviewing various strategies for detecting and treating pathogenic bacterial infections using M NCs, summarizing the antibacterial effects of these nanoantibiotics on wound infections, biofilms, and oral infections. Finally, we propose a perspective on the remaining challenges and future developments of M NCs for bacterial infectious therapy.

1. Introduction

In recent years, there has been an incessant emergence of infectious and lethal pathogenic microorganisms, including Escherichia coli (E. coli), Staphylococcus, Salmonella, Botox, and other pathogenic bacteria, as well as the SARS virus, Ebola virus, and Zika virus [1]. The widespread infection and transmission of these pathogenic microorganisms have posed serious threats to human safety and normal life. The global spread of COVID-19 at the end of 2019 has brought about a profound realization of this issue [2]. In 2020, the World Health Organization (WHO) published the 2019 Global Health Estimations Report, which identified the leading causes of mortality worldwide in 2019 [3]. Among them, respiratory infections ranked fourth as a cause of death due to infectious diseases, primarily caused by pathogenic bacteria, fungi, and viruses. Although some antimicrobial drugs have provided temporary solutions for human infectious diseases, prolonged usage and misuse of these drugs have led to evolutionary adaptations and mutations in pathogenic microorganisms during treatment, resulting in resistance towards one or more drugs [4]. Consequently, microbial resistance presents a significant challenge to global public health.
The development of novel antibiotics presents a viable approach to address the issue of bacterial resistance. However, it is important to acknowledge that antibiotic development is a challenging and time-consuming process that may inadvertently contribute to the emergence of more resilient bacterial strains [5]. Thus, there is an urgent need for exploration and identification of alternative antibacterial agents as substitutes for conventional antibiotics. With the development of nanotechnology, a series of materials ranging in size from 1 to 100 nm have been sequentially synthesized, exhibiting diverse shapes, sizes, and properties [6,7]. These novel attributes bestow them with unique characteristics suitable for various biomedical applications. Nano-antibacterial materials are a class of functional materials that exhibit antibacterial activity through precise manipulation of their size, surface chemistry, and structural morphology [8]. Additionally, they can serve as carriers to enhance the efficacy and safety of antibacterial drugs [8]. Examples include non-metallic nanomaterials like graphene [9] and carbon nanotubes [10], as well as metal-based nanomaterials primarily composed of gold [11], silver [12], copper [13], etc. [14,15,16]. These nanomaterials, known as “nanoantibiotics” [17], possess antibacterial properties and can serve as alternatives to conventional antibiotics. Recently, the rapid development of nanotechnology has revolutionized various aspects of human life. Nanoantibiotics, mainly composed of nano-antibacterial materials, play a pivotal role in combating bacterial infections and offer new prospects for treating human diseases.
Metal nanomaterials, including nanoparticles (NPs) and nanoclusters (NCs), find extensive applications in catalysis, sensing, and biomedical fields owing to their distinctive physical and chemical properties [18]. Metal nanoparticles (M NPs) possess unique optical, electrical, and catalytic properties, along with excellent stability within the size range of 10–100 nm [19]. Metal nanoclusters (M NCs), which consist of several or hundreds of atoms with a particle size below 3 nm, represent an intermediate structure between molecules and nanoparticles [18] (Figure 1). Compared with M NPs, M NCs exhibit unique electronic and optical properties, as well as strong quantum size effects [19,20]. It has been reported that metal nanomaterials can exert antibacterial effects on pathogenic bacteria by causing enzyme inactivation, metabolic disorders, destruction of cellular electrons, and disruption of substance transport and respiratory systems [21,22]. Due to the toxic side effects of traditional metal nanoparticles on normal human cells, their application in the biomedical field is limited. However, M NCs, owing to their ultra-small molecule-like structure, can be easily cleared by the kidneys, thereby significantly reducing the toxicity and side effects of these materials [23]. Moreover, M NCs do not exhibit drug resistance in disease treatment and demonstrate excellent biosafety [24]. Xie’s group conducted comprehensive research on the design, synthesis, and performance evaluation of M NCs with different structures [25,26,27]. These M NCs demonstrate broad-spectrum antibacterial properties against various bacterial strains, thereby expanding their potential applications in biomedical and environmental engineering. In this review, we outline the development and research progress on multifunctional M NCs for bacterial infection and emphasize the mechanisms of action associated with the designed diagnostic and therapeutic agents. Finally, the challenges and perspectives of M NCs toward bacterial infection applications are discussed.

2. Synthesis and Properties of M NCs

M NCs are nanomaterials with metal as the core and a surface modified by different organic ligands, which are transition states between atoms and nanoparticles (Figure 2) [18]. They have a precise atomic composition and structure, and ligand-protected M NCs can be represented by a “molecular formula” such as [Mn(SR)m]q (where m, n, and q are the number of metal atoms (M), ligands (SR), and net charge in the M NC, respectively) [18]. According to different synthesis pathways, M NCs can be classified into two methods, namely “bottom-up” and “top-down” methods [28]. The former typically involves the reduction of metal ions (Mn+) to metal atoms (M0) in the presence of reducing agents (such as NaBH4), followed by gradual nucleation and growth on the ligand surface to achieve the desired size of M NCs [29]. At present, the “bottom-up” approach is widely employed for synthesizing M NCs due to its advantages of high yield, rapid synthesis time, and straightforward reaction process. However, precise control over reduction kinetics remains crucial in achieving high-quality M NCs [30]. The “top-down” process involves the synthesis of ultra-small M NCs by utilizing ligands to etch large-sized nanoparticles, thereby necessitating a specific reaction environment to facilitate controlled etching reactions [31]. Consequently, in comparison to the “bottom-up” approach, the “top-down” method is characterized by increased time requirements and reduced yields.
Currently, the organic ligands commonly used for synthesizing M NCs are mainly thiol groups, because the sulfur atoms in the ligands can form strong covalent bonds with the metal atoms, which can provide good protection for M NCs [32]. Many M NCs with precise atomic numbers have been reported, such as Au NCs [33], Ag NCs [34], Cu NCs [35], and Pt NCs [36], as well as binary or multivariate nanoclusters formed by these metal complexes [37], which are widely used in various biomedical fields due to their respective advantages and disadvantages (Figure 3) [38]. For instance, Ag NCs have the advantages of high stability, broad-spectrum antimicrobial activity, and availability of a track record of biological use, but they are limited by their comparatively high cost, relatively low abundance in nature, and lack of endogenous functions of Ag. In contrast, Au NCs exhibit chemical inertness, ease of chemical synthesis, low toxicity, and availability of a track record of biological use. Nevertheless, they also face challenges such as comparatively high cost, relatively low abundance in nature, and lack of endogenous functions of Au [38].

3. Application of M NCs in Bacterial Infection

3.1. Detection of Pathogens by M NCs

Before taking measures for treatment after bacterial infection, accurate and rapid detection and identification of pathogenic bacteria are also particularly important. Due to the lack of timely diagnostic methods, many patients face significant challenges in effectively diagnosing drug-resistant bacteria as their condition worsens after bacterial infection. The conventional strategies for bacterial detection include plate counting, biochemical analysis, polymerase chain reaction (PCR) technology, and gene sequencing technology. However, these techniques often rely on expensive and time-consuming high-end instruments [39]. In contrast, the utilization of M NCs in biosensing has gained significant attention due to their simple synthesis process, excellent biocompatibility, strong photoluminescence properties, high photostability characteristics, and facile functionalization with other biomolecules [40]. M NCs not only enable the detection of various biomolecules, such as nucleic acids, proteins, urea glucose glutathione, etc., but also facilitate rapid and efficient identification of pathogenic bacteria through diverse strategies (Figure 4) [41,42].

3.1.1. Label-Free Detection

Photoluminescence is one of the most important properties of M NCs, and it is also the foundation for their applications in the biomedical field. Due to the size of M NCs being comparable to the Fermi wavelength of electrons and their generation of quantum size effects, the energy levels become discontinuous and discrete, similar to those of molecules [37]. Therefore, M NCs do not exhibit the characteristic of surface plasmon resonance absorption but exhibit luminescent properties across the visible to near-infrared light spectrum. The emergence of this luminescent behavior is attributed to electronic transitions resulting from energy splitting, including both intra-band and inter-band transitions [37]. At present, an increasing number of biomolecules containing thiol groups are being employed for the synthesis of luminescent M NCs, harnessing their luminescent properties for pathogenic bacterial detection [43,44]. Chan et al. [45] employed human serum albumin (HSA)-protected gold nanoclusters (HAS-Au NCs) as fluorescent probes to detect Staphylococcus aureus (S. aureus) and methicillin-resistant S. aureus (MRSA). The results showed that HAS-Au NCs only exhibited a highly specific binding ability toward S. aureus and MRSA, leading to a substantial enhancement in fluorescence intensity (Figure 5A), which enables qualitative and quantitative analysis and detection of S. aureus. Yan et al. [46] developed an “on–off–on” fluorescent Au NC probe (BSA-Au NCs), which emitted a clear, red fluorescence under UV excitation (on) and quenched in the presence of Cu2+ (off). When the E. coli was present in media, the specific binding between Cu2+ and E. coli reduced the concentration of Cu2+ in the system, leading to the recovery of BSA-Au NC fluorescence (on) from Cu2+-induced quenching (Figure 5B). Applying this principle, a trace amount of E. coli in artificial sewage was detected within 30 min, with a lowest detectable concentration of 89 CFU/mL. In addition, Liu et al. [47] developed a rapid synthesis method of cross-linked protein-modified GC-Au NCs, which could quickly assemble into larger rod-shaped structures. Given that proteins are typical amphoteric electrolytes, the surface charge of GC-Au NCs could be regulated by environmental pH, enabling enabled enhanced adhesion between nanoclusters and E. coli cells (Figure 5C). Zheng et al. [48] used the coagulation effect between bacteria and M NCs to fabricate glutathione-protected Au-Ag alloy nanoclusters, wherein Ag+ doping significantly enhanced the photoluminescence intensity of Au NCs. The results (Figure 5D) demonstrated that the fluorescence intensity of Au-Ag NCs could be rapidly quenched by selective aggregation of nanoclusters and Acinetobacter baumannii (A. baumannii) while exhibiting no impact on the other eight pathogens, achieving unlabeled detection with an LOD of 2.3 × 103 CFU/mL for A. baumannii. The above studies can provide valuable insights for rapid analysis and detection of different pathogenic bacteria, but the interaction mechanism between bacteria and nanoclusters still needs further research.

3.1.2. Molecular Recognition

The main drawback of fluorescent M NCs for bacterial detection is that their selectivity is not ideal. To overcome this challenge, a commonly employed approach involves the modification of M NCs using ligands that can recognize bacterial cell receptors [49]. Cheng et al. [50] developed a dual recognition strategy for S. aureus detection by designing nucleic acid aptamer-modified magnetic beads (Apt-MBs) and Au NCs protected by vancomycin (Van) (Au NCs@Van) (Figure 6A). It was demonstrated that Van could specifically identify S. aureus among four different pathogenic bacteria, leading to fluorescence generation upon interaction, followed by specific binding of the adapter on the magnetic bead to the bacterial membrane. Under the driving force of the magnetic field, the beads separated from other bacteria and recovered the fluorescence of the M NCs through washing with NaOH. The proposed method enabled the quantitative detection of S. aureus concentration in milk and human serum with high selectivity and a low LOD (70 CFU/mL). Yang et al. [51] designed fluorescent Ag NCs (Nx-Ag NCs/Apt-G) with both detection and bactericidal functions, which utilized DNA as a template and were modified with specific recognition aptamers toward S. aureus. As shown in Figure 6B, Nx-Ag NCs/Apt-G exhibited pronounced fluorescence intensity upon excitation at 365 nm, which diminished when the adapter on the nanoclusters’ surface interacted with S. aureus through specific binding, leading to separation of the adapter from the M NCs. Simultaneously, the M NCs exhibited significant bactericidal effects on both Gram-negative and Gram-positive bacteria, demonstrating broad-spectrum antibacterial activity. Researchers have also explored the utilization of antimicrobial peptides [52], signaling molecules [53], enzymes [54], etc., for the modification of M NCs to enable bacterial detection through recognition interactions between these biomolecules and bacteria.

3.1.3. Sensor Array

The aforementioned methods are all designed for the detection of a single type of bacteria, whereas clinical infections often involve multiple pathogenic bacteria. Therefore, there is a need to develop sensors capable of simultaneously detecting different types of bacteria. The array-based “chemical nose/tongue” sensing method employs the collective signal characteristics generated by multiple non-selective probes to differentiate analytes, thereby enabling the detection of diverse bacterial species [55]. Ji et al. [55] synthesized four fluorescent Au NCs using human serum albumin (HSA), lysozyme (Lyz), lactoferrin (Lf), and vancomycin-modified human serum albumin (Van) as templates. These four biomolecules have a certain affinity for peptides, receptors, and polysaccharides on the surface of bacteria, which is related to the charge, hydrophobicity, and hydrophilicity of M NCs. The differences in affinity between different bacteria and various Au NCs were used to distinguish and classify multiple bacteria. As shown in Figure 7, by measuring the change in fluorescence in the supernatant after the interaction of Au NCs with bacteria and using linear discriminant analysis, the sensor array successfully identified six bacterial species (S. aureus, MRSA, E. coli, KREC, B. subtilis, and A. faecalis) encompassing two drug-resistant strains with an accuracy of 93.3%. This sensor array has the advantages of easy synthesis, convenient use, and high diagnostic ability, which can provide a simple, fast, and accurate diagnosis of bacterial infections in resource-limited environments. Consequently, it holds immense potential for applications in disease diagnosis and treatment, as well as food safety and environmental monitoring.

3.2. The Antibacterial Effect of M NCs

Metal nanomaterials have been proven to possess significant antibacterial activity, particularly Ag nanoparticles, which primarily release metal ions to achieve bactericidal effects and do not engender bacterial drug resistance [56]. However, the particle size of these metal nanomaterials is typically large, rendering them prone to accumulation within living organisms and impeding clearance by organs such as the kidneys [57]. When metal nanomaterials are reduced to the size range of nanoclusters, not only can they be efficiently eliminated from the body, but they also exhibit enhanced antibacterial activity compared to nanoparticles [58]. This augmented antibacterial behavior is attributed to the critical internalized “size cutoff” effect (Figure 8). Ultra-small M NCs can efficiently penetrate the bacterial cell walls through their pores, facilitating internal absorption by bacteria and minimizing the interception of larger nanoparticles outside the cellular environment. On one hand, the decomposition of M NCs can generate electrons, thereby activating O2 and inducing the production of reactive oxygen species (ROS), which subsequently oxidize bacterial membranes. On the other hand, damaged bacterial membranes further facilitate the internalization of M NCs and their continuous accumulation, leading to interference with normal bacterial metabolism [58]. By harnessing this antibacterial mechanism, increasing research efforts have been devoted to designing multifunctional M NCs with diverse ligand modifications and the hybridization of different nanomaterials (Table 1) to address challenges associated with bacterial infections.

3.3. Antibacterial Infectious Therapy for M NCs

3.3.1. Promoting Wound Healing and Eliminating Inflammation

After skin tissue injury, the affected area is susceptible to bacterial infection. Failure to promptly address this issue can result in delayed wound healing and ulceration. M NC materials have been extensively employed to enhance the healing process of external wounds. Zheng et al. [24] developed four types of Au NCs (AuDAMP, AuAMP, AuAHMP, and AuDHMP) with thiopyrimidine as a ligand. The amino structures present in the first three ligands conferred stronger positive charges upon Au NCs and exhibited potent bactericidal effects against both Gram-negative and Gram-positive bacteria (Figure 9). In a mouse wound model infected with MRSA, the results showed that AuDAMP had a good therapeutic effect on wound healing, mainly attributed to the enzymatic activity of the Au NCs that facilitated the production of ROS. Li et al. [77] reported that M NCs could effectively alleviate the inflammatory response in wounds, thereby promoting wound healing and the proliferation and migration of related cells. In our previous work, multifunctional fluorescent Au NCs (AuxGSH-HHC10) with both AIE properties and antibacterial properties were prepared with glutathione (GSH) and cationic antimicrobial peptide (HHC10) [78]. They could achieve in vitro imaging of Gram-negative and Gram-positive bacteria and also exhibited broad-spectrum antibacterial effects on these two types of bacteria without developing drug resistance. The results of in vivo wound infection experiments indicated that AuxGSH-HHC10 could not only reduce the incidence of inflammation but also kill bacteria at the infection site and induce rapid repair of wound tissue.

3.3.2. Clearing Biofilm and Preventing Its Formation

Bacteria can aggregate and secrete an extracellular matrix consisting of DNA, polysaccharides, proteins, lipids, etc., on a specific surface to form a three-dimensional polymer network structure. These extracellular matrices facilitate bacterial adhesion and subsequent formation of microcolonies that progressively grow, mature, and develop into biofilms [79]. The formation of biofilms protects bacteria from attacks by antibiotics and the host immune system, leading to bacterial resistance to antibiotics and increasing the difficulty of treating bacterial infections in clinical practice. M NCs, due to their small size, can penetrate biofilms and avoid bacterial tolerance, making them ideal materials for anti-biofilm applications [57]. Xie et al. [72] developed DNase-functionalized gold nanoclusters (DNase–Au NCs) based on extracellular DNA, which is one of the main components of biofilms. When the nanoclusters interacted with the biofilm formed by S. aureus and P. aeruginosa, DNase could decompose the extracellular DNA matrix, thus exposing defenseless bacteria. Then, under the irradiation of near-infrared light (808 nm), Au NCs exerted photodynamic and photothermal antibacterial effects. The biofilm removal capacity was up to 80%, and the bactericidal capacity was up to about 90% (Figure 10). Similarly, Okamoto et al. [73] developed a novel photosensitizer based on Au NCs to effectively inhibit the formation of bacterial biofilms associated with oral caries. The hybrid nanomaterial (Lys-AU NCs/RB) had lysozyme (Lys)-modified Au NCs as its core and was connected with light-sensitive molecule Rose red (RB). Under the irradiation of LED light, on the one hand, Au NCs transferred their own energy to RB through energy resonance transfer so that the photosensitizer could efficiently produce singlet oxygen to kill bacteria; on the other hand, Au NCs exhibited inherent antibacterial activity, and their synergistic effect effectively eliminated bacteria prior to biofilm maturation.

3.3.3. Treating Oral Bacterial Infections

With the continuous popularization of oral health and hygiene, people are paying more and more attention to their oral problems. Although various diseases caused by oral bacterial infection, such as dental caries and periodontitis, are not fatal, they have high incidences and long-term characteristics [80]. Considering the remarkable contributions of nanomaterials in treating bacterial infections, researchers have initiated investigations into employing diverse nano-functional materials for the management of oral diseases [81]. However, the use of M NCs in addressing oral bacterial infections is still at an early stage of development. Streptococcus mutans (S. mutans) is a prominent pathogen responsible for dental caries. The quaternary ammonium salt-modified gold nanoclusters (QA-GNCs) developed by Xie et al. [68] not only effectively treat in vivo bacterial infections caused by MRSA but also exhibit antibacterial effects comparable to those of vancomycin at remarkably low concentrations (5 μg/mL). Coating these nanoclusters on transparent orthodontic appliances used for correcting malocclusion could efficiently prevent the formation of S. mutans biofilms on their surfaces [82]. In addition, the nanoclusters exhibited excellent biosafety and retained their anti-biofilm activity even after being reused more than three times within a three-month period. Wu et al. [83] modified Pt NCs with catalytic activity on g-C3N4 nanosheets (CN-Pt NCs), and the resulting nanozyme system showed dual oxidase-like and peroxidase-like activities and was used in the treatment of biofilm-induced periodontitis (Figure 11). Enzymatic property analysis revealed that CN-Pt NCs not only efficiently catalyze O2 to color TMB but also effectively catalyze H2O2 to color TMB, demonstrating excellent enzymatic catalytic performance. Using this enzyme property, CN-Pt NCs could effectively prevent the formation of dental plaque in the treatment of oral periodontitis and reduce inflammation and bone loss, on the other hand, showing a better therapeutic effect than clinical oral drugs (e.g., periocline).

4. Conclusions and Perspectives

The treatment of bacterial infections faces two major challenges, namely antibiotic resistance resulting from the overuse of antibiotics and the formation of biofilms at specific interfaces. The former creates a dilemma whereby certain superbugs cannot be treated due to a lack of effective drugs, while the latter provides a protective barrier for bacteria in the extracellular matrix, thereby reducing the efficacy of antibiotics. Consequently, it is imperative to explore novel antibacterial strategies as alternatives to traditional antibiotic therapy. In recent years, an increasing number of nanoantibiotics based on nanomaterials with antibacterial properties have been developed to address issues related to bacterial resistance and eradicate biofilms. In the present review, we provide a comprehensive overview of the synthesis methods and physicochemical properties of M NCs, with a focus on the current application status in bacterial infections, including pathogen detection and therapy. The synthesis methods of M NCs include bottom-up and top-down approaches, each with its own advantages and disadvantages. The prepared M NCs exhibit excellent optical properties, enabling them to achieve quantitative and qualitative detection and imaging of pathogens through label-free detection, molecular recognition, and the use of sensor arrays. Nanoantibiotics based on M NCs can also exert bactericidal effects on pathogens through mechanisms such as membrane damage, release of metal ions, generation of ROS, and disruption of intracellular components. In addition, M NPs can be used alone or in combination with other antibacterial agents and functional materials and are widely used to promote wound healing and eliminate inflammation, clear biofilms and prevent their formation, and treat oral bacterial infections.
Although significant progress has been made in research on M NCs as nanoantibiotics in recent years, there are still some key challenges to be addressed in the future. (1) Although numerous M NCs have been designed through atomic precision engineering, there are few types that can be used as nanoantibiotics, and their applications as traceable antimicrobial agents are still limited. (2) Although the antibacterial mechanism of M NCs has been systematically studied, the understanding of dynamic nano-biological interactions is still insufficient. (3) The effectiveness of M NCs in combating antibiotic resistance and the mechanisms to prevent resistance are issues that need to be considered in their clinical application. (4) The enzymatic-like activity of M NCs is lower compared to that of other metal materials, so constructing M NC nanozymes with high catalytic activity through atomic precision nano-chemistry will help improve the application of MNCs in disease diagnosis and therapy. (5) Although studies have reported that Au NCs can be eliminated from the body through the kidneys, residual Au NCs remain a problem in engineering designs for in vivo treatment and diagnosis, and the biological toxicity of other M NCs remains a huge challenge. We firmly believe that the collaborative efforts of scientists from diverse fields, including nanobiotechnology, material chemistry, pharmacy, and clinical medicine, hold immense potential in addressing the critical challenge posed by multidrug-resistant bacterial infections through the development of antibacterial M NCs as highly effective next-generation nanoantibiotics.

Author Contributions

Conceptualization, Z.G. and L.J.; methodology, Y.W. (Yuxian Wang), M.G., J.C. and Y.W. (Yusong Wan); validation, Y.W. (Yuxian Wang), M.G. and J.C.; formal analysis and investigation, Y.W. (Yusong Wan) and L.Z.; writing—original draft preparation, Y.W. (Yuxian Wang) and M.G.; writing—review and editing, L.Z., Z.G. and L.J.; funding acquisition, Y.W. (Yuxian Wang) and L.J. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (2021YFC2102700, U2106228), the Jiangsu Synergetic Innovation Center for Advanced Bio-Manufacture (XTC2205), the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (23KJB550007), the Project funded by the China Postdoctoral Science Foundation (2023M741669), the Jiangsu Funding Program for Excellent Postdoctoral Talent (2023ZB025), and the College Students’ Innovative Entrepreneurial Training Plan Program (2024102911518).

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Willyard, C. The drug-resistant bacteria that pose the greatest health threats. Nature 2017, 543, 15. [Google Scholar] [CrossRef]
  2. Shereen, M.A.; Khan, S.; Kazmi, A.; Bashir, N.; Siddique, R. COVID-19 infection: Emergence, transmission, and characteristics of human coronaviruses. J. Adv. Res. 2020, 24, 91–98. [Google Scholar] [CrossRef]
  3. Thompson, T. The staggering death toll of drug-resistant bacteria. Nature 2022. Available online: https://www.nature.com/articles/d41586-022-00228-x (accessed on 27 June 2024). [CrossRef]
  4. Cheng, G.; Dai, M.; Ahmed, S.; Hao, H.; Wang, X.; Yuan, Z. Antimicrobial drugs in fighting against antimicrobial resistance. Front. Microb. 2016, 7, 470. [Google Scholar] [CrossRef]
  5. Theuretzbacher, U.; Bush, K.; Harbarth, S.; Paul, M.; Rex, J.H.; Tacconelli, E.; Thwaites, G.E. Critical analysis of antibacterial agents in clinical development. Nat. Rev. Microbiol. 2020, 18, 286–298. [Google Scholar] [CrossRef]
  6. Zhao, N.; Yan, L.; Zhao, X.; Chen, X.; Li, A.; Zheng, D.; Zhou, X.; Dai, X.; Xu, F. Versatile types of organic/inorganic nanohybrids: From strategic design to biomedical applications. Chem. Rev. 2018, 119, 1666–1762. [Google Scholar] [CrossRef]
  7. Jian, W.; Hui, D.; Lau, D. Nanoengineering in biomedicine: Current development and future perspectives. Nanotechnol. Rev. 2020, 9, 700–715. [Google Scholar] [CrossRef]
  8. Makabenta, J.M.V.; Nabawy, A.; Li, C.H.; Schmidt-Malan, S.; Patel, R.; Rotello, V.R. Nanomaterial-based therapeutics for antibiotic-resistant bacterial infections. Nat. Rev. Microbiol. 2021, 19, 23–36. [Google Scholar] [CrossRef]
  9. Seifi, T.; Kamali, A.R. Anti-pathogenic activity of graphene nanomaterials: A review. Colloids Surf. B 2021, 199, 111509. [Google Scholar] [CrossRef]
  10. Xin, Q.; Shah, H.; Nawaz, A.; Xie, W.; Akram, M.Z.; Batool, A.; Tian, L.; Jan, S.U.; Boddula, R.; Guo, B.; et al. Antibacterial carbon-based nanomaterials. Adv. Mater. 2019, 31, 1804838. [Google Scholar] [CrossRef]
  11. Su, C.; Huang, K.; Li, H.; Lu, Y.; Zheng, D. Antibacterial properties of functionalized gold nanoparticles and their application in oral biology. J. Nanomater. 2020, 2020, 1–13. [Google Scholar]
  12. Zheng, K.; Setyawati, M.I.; Leong, D.T.; Xie, J. Antimicrobial silver nanomaterials. Coord. Chem. Rev. 2018, 357, 1–17. [Google Scholar] [CrossRef]
  13. Woźniak-Budych, M.J.; Staszak, K.; Staszak, M. Copper and copper-based nanoparticles in medicine-perspectives and challenges. Molecules 2023, 28, 6687. [Google Scholar] [CrossRef]
  14. Vimbela, G.V.; Ngo, S.M.; Fraze, C.; Yang, L.; Stout, D.A. Antibacterial properties and toxicity from metallic nanomaterials. Int. J. Nanomed. 2017, 12, 3941–3965. [Google Scholar] [CrossRef]
  15. El-Meligy, M.A.; Abd El-Monaem, E.M.; Eltaweil, A.S.; Mohy-Eldin, M.S.; Ziora, Z.M.; Heydari, A.; Omer, A.M. Recent advancements in metallic Au- and Ag-based chitosan nanocomposite derivatives for enhanced anticancer drug delivery. Molecules 2024, 29, 2393. [Google Scholar] [CrossRef]
  16. Xie, M.; Gao, M.; Yun, Y.; Malmsten, M.; Rotello, V.M.; Zboril, R.; Akhavan, O.; Kraskouski, A.; Amalraj, J.; Cai, X.; et al. Antibacterial nanomaterials: Mechanisms, impacts on antimicrobial resistance and design principles. Angew. Chem. Int. Ed. 2023, 62, e202217345. [Google Scholar] [CrossRef]
  17. 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]
  18. Jin, R.; Zeng, C.; Zhou, M.; Chen, Y. Atomically precise colloidal metal nanoclusters and nanoparticles: Fundamentals and opportunities. Chem. Rev. 2016, 116, 10346–10413. [Google Scholar] [CrossRef]
  19. Borghei, Y.S.; Hosseinkhani, S.; Ganjali, M.R. Bridging from metallic nanoclusters to biomedical in understanding physicochemical interactions at the nano–bio interface. Part. Part. Syst. Charact. 2022, 39, 2100202. [Google Scholar] [CrossRef]
  20. Du, X.; Jin, R. Atomically precise metal nanoclusters for catalysis. ACS Nano 2019, 13, 7383–7387. [Google Scholar] [CrossRef]
  21. Xue, X.; Wang, Y.; Yang, H. Preparation and characterization of boron-doped titania nano-materials with antibacterial activity. Appl. Surf. Sci. 2013, 264, 94–99. [Google Scholar] [CrossRef]
  22. Niu, M.; Liu, X.; Dai, J.; Hou, W.; Wei, L.; Xu, B. Molecular structure and properties of wool fiber surface-grafted with nano-antibacterial materials. Spectrochim. Acta Part A 2012, 86, 289–293. [Google Scholar] [CrossRef]
  23. Loynachan, C.N.; Soleimany, A.P.; Dudani, J.S.; Lin, Y.; Najer, A.; Bekdemir, A.; Chen, Q.; Bhatia, S.N.; Stevens, M.M. Renal clearable catalytic gold nanoclusters for in vivo disease monitoring. Nat. Nanotechnol. 2019, 14, 883–890. [Google Scholar] [CrossRef]
  24. Zheng, Y.; Liu, W.; Qin, Z.; Chen, Y.; Jiang, H.; Wang, X. Mercaptopyrimidine-conjugated gold nanoclusters as nanoantibiotics for combating multidrug-resistant superbugs. Bioconjugate Chem. 2018, 29, 3094–3103. [Google Scholar] [CrossRef]
  25. Zheng, K.; Xie, J. Composition-dependent antimicrobial ability of full-spectrum AuxAg25-x Alloy nanoclusters. ACS Nano 2020, 14, 11533–11541. [Google Scholar] [CrossRef]
  26. Zheng, K.; Xie, J. Engineering ultrasmall metal nanoclusters as promising theranostic agents. Trends Chem. 2020, 2, 665–679. [Google Scholar] [CrossRef]
  27. Zheng, K.; Setyawati, M.I.; Leong, D.T.; Xie, J. Overcoming bacterial physical defenses with molecule-like ultrasmall antimicrobial gold nanoclusters. Bioact. Mater. 2021, 6, 941–950. [Google Scholar] [CrossRef]
  28. Zheng, K.; Yuan, X.; Goswami, N.; Zhang, Q.; Xie, J. Recent advances in the synthesis, characterization, and biomedical applications of ultrasmall thiolated silver nanoclusters. RSC Adv. 2014, 4, 60581–60596. [Google Scholar] [CrossRef]
  29. Yao, Q.; Cao, Y.; Chen, T.; Xie, J. Total synthesis of thiolate-protected noble metal nanoclusters. In Atomically Precise Nanochemistry; WILEY Publishing: Hoboken, NJ, USA, 2023. [Google Scholar]
  30. Goswami, N.; Yao, Q.; Chen, T.; Xie, J. Mechanistic exploration and controlled synthesis of precise thiolate-gold nanoclusters. Coord. Chem. Rev. 2016, 329, 1–15. [Google Scholar] [CrossRef]
  31. Pandit, S.; Kundu, S. Methods of synthesis of metal nanoclusters. In Luminescent Metal. Nanoclusters; Woodhead Publishing: Sawston, UK, 2022; pp. 17–55. [Google Scholar]
  32. Yao, Q.; Wu, Z.; Liu, Z.; Lin, Y.; Yuan, X.; Xie, J. Molecular reactivity of thiolate-protected noble metal nanoclusters: Synthesis, self-assembly, and applications. Chem. Sci. 2021, 12, 99–127. [Google Scholar] [CrossRef]
  33. Cao, Y.; Fung, V.; Yao, Q.; Chen, T.; Zang, S.; Jiang, D.; Xie, J. Control of single-ligand chemistry on thiolated Au25 nanoclusters. Nat. Commun. 2020, 11, 5498. [Google Scholar] [CrossRef] [PubMed]
  34. Jana, A.; Jash, M.; Poonia, A.K.; Paramasivam, G.; Islam, M.R.; Chakraborty, P.; Antharjanam, S.; Machacek, J.; Ghos, S.; Adarsh, K.N.; et al. Light-activated intercluster conversion of an atomically precise silver nanocluster. ACS Nano 2021, 15, 15781–15793. [Google Scholar] [CrossRef]
  35. Rong, W.; Zou, H.; Zang, W.; Xi, S.; Wei, S.; Long, B.; Hu, J.; Ji, Y.; Duan, L. Size-dependent activity and selectivity of atomic-level copper nanoclusters during CO/CO2 electroreduction. Angew. Chem. Int. Ed. 2021, 60, 466–472. [Google Scholar] [CrossRef]
  36. Duan, X.; Cao, F.; Ding, R.; Li, Q.; Aisha, R.; Zhang, S.; Hua, K.; Rui, Z.; Wu, Y.; Li, J.; et al. Cobalt-doping stabilized active and durable sub-2 nm Pt nanoclusters for low-Pt-loading PEMFC cathode. Adv. Energy Mater. 2022, 12, 2103144. [Google Scholar] [CrossRef]
  37. Su, Y.; Xue, T.; Liu, Y.; Qi, J.; Jin, R.; Lin, Z. Luminescent metal nanoclusters for biomedical applications. Nano Res. 2019, 12, 1251–1265. [Google Scholar] [CrossRef]
  38. Lai, W.F.; Wong, W.T.; Rogach, A.L. Development of copper nanoclusters for in vitro and in vivo theranostic applications. Adv. Mater. 2020, 32, 1906872. [Google Scholar] [CrossRef]
  39. Tang, M.; Zhang, J.; Yang, C.; Zheng, H.; Jiang, H. Gold nanoclusters for bacterial detection and infection therapy. Front. Chem. 2020, 8, 181. [Google Scholar] [CrossRef]
  40. Yang, L.; Hou, P.; Wei, J.; Li, B.; Gao, A.; Yuan, Z. Recent advances in gold nanocluster-based biosensing and therapy: A review. Molecules 2024, 29, 1574. [Google Scholar] [CrossRef] [PubMed]
  41. Tao, Y.; Li, M.; Ren, J.; Qu, X. Metal nanoclusters: Novel probes for diagnostic and therapeutic applications. Chem. Soc. Rev. 2015, 44, 8636–8663. [Google Scholar] [CrossRef]
  42. Li, D.; Kumari, B.; Makabenta, J.M.; Gupta, A.; Rotello, V. Effective detection of bacteria using metal nanoclusters. Nanoscale 2019, 11, 22172–22181. [Google Scholar] [CrossRef]
  43. Qian, S.; Wang, Z.; Zuo, Z.; Wang, X.; Wang, Q.; Yuan, X. Engineering luminescent metal nanoclusters for sensing applications. Coord. Chem. Rev. 2022, 451, 214268. [Google Scholar] [CrossRef]
  44. Xiao, Y.; Wu, Z.; Yao, Q.; Xie, J. Luminescent metal nanoclusters: Biosensing strategies and bioimaging applications. Aggregate 2021, 2, 114–132. [Google Scholar] [CrossRef]
  45. Chan, P.H.; Chen, Y.C. Human serum albumin stabilized gold nanoclusters as selective luminescent probes for Staphylococcus aureus and methicillin-resistant Staphylococcus aureus. Anal. Chem. 2012, 84, 8952–8956. [Google Scholar] [CrossRef] [PubMed]
  46. Yan, R.; Shou, Z.; Chen, J.; Wu, H.; Zhao, Y.; Qiu, L.; Jiang, P.; Mou, X.; Wang, J.; Li, Y. On-off-on gold nanocluster-based fluorescent probe for rapid Escherichia coli differentiation, detection and bactericide screening. ACS Sustain. Chem. Eng. 2018, 6, 4504–4509. [Google Scholar] [CrossRef]
  47. Liu, P.; Wang, H.; Hiltunen, J.K.; Chen, Z.; Shen, J. Cross-linked proteins with gold nanoclusters: A dual-purpose pH-responsive material for controllable cell Imaging and antibiotic delivery. Part. Part. Syst. Charact. 2015, 32, 749–755. [Google Scholar] [CrossRef]
  48. Zheng, Y.; Wang, X.; Jiang, H. Label-free detection of Acinetobacter baumannii through the induced fluorescence quenching of thiolated AuAg nanoclusters. Sens. Actuators B 2018, 277, 388–393. [Google Scholar] [CrossRef]
  49. Kailasa, S.K.; Borse, S.; Koduru, J.R.; Murthy, Z.V.P. Biomolecules as promising ligands in the synthesis of metal nanoclusters: Sensing, bioimaging and catalytic applications. Trends Environ. Anal. Chem. 2021, 32, e00140. [Google Scholar] [CrossRef]
  50. Cheng, D.; Yu, M.; Fu, F.; Han, W.; Li, G.; Xie, J.; Song, Y.; Swihart, M.T.; Song, E. Dual recognition strategy for specific and sensitive detection of bacteria using aptamer-coated magnetic beads and antibiotic-capped gold nanoclusters. Anal. Chem. 2016, 88, 820–825. [Google Scholar] [CrossRef]
  51. Yang, M.; Chen, X.; Zhu, L.; Lin, S.; Li, C.; Li, X.; Huang, K.; Xu, W. Aptamer-functionalized DNA–silver nanocluster nanofilm for visual detection and elimination of bacteria. ACS Appl. Mater. Interfaces 2021, 13, 38647–38655. [Google Scholar] [CrossRef]
  52. Hossein-Nejad-Ariani, H.; Kim, T.; Kaur, K. Peptide-based biosensor utilizing fluorescent gold nanoclusters for detection of Listeria monocytogenes. ACS Appl. Nano Mater. 2018, 1, 3389–3397. [Google Scholar] [CrossRef]
  53. Chahande, A.M.; Lathigara, D.; Prabhune, A.A.; Devi, R.N. Red fluorescent ultra-small gold nanoclusters functionalized with signal molecules to probe specificity in quorum sensing receptors in gram-negative bacteria. Arch. Microbiol. 2021, 203, 4293–4301. [Google Scholar] [CrossRef] [PubMed]
  54. Chang, X.; Gao, P.; Li, Q.; Liu, H.; Hou, H.; Wu, S.; Chen, J.; Gan, L.; Zhao, M.; Zhang, D.; et al. Fluorescent papain-encapsulated platinum nanoclusters for sensing lysozyme in biofluid and gram-positive bacterial identification. Sens. Actuators B 2021, 345, 130363. [Google Scholar] [CrossRef]
  55. Ji, H.; Wu, L.; Pu, F.; Ren, J.; Qu, X. Point-of-care identification of bacteria using protein-encapsulated gold nanoclusters. Adv. Healthc. Mater. 2018, 7, 1701370. [Google Scholar] [CrossRef] [PubMed]
  56. Gold, K.; Slay, B.; Knackstedt, M.; Gaharwar, A.K. Antimicrobial activity of metal and metal-oxide based nanoparticles. Adv. Ther. 2018, 1, 1700033. [Google Scholar] [CrossRef]
  57. Li, D.; Kumari, B.; Makabenta, J.M.; Tao, B.; Qian, K.; Mei, X.; Rotello, V.M. Development of coinage metal nanoclusters as antimicrobials to combat bacterial infections. J. Mater. Chem. B 2020, 8, 9466–9480. [Google Scholar] [CrossRef] [PubMed]
  58. Zheng, K.; Xie, J. Cluster materials as traceable antibacterial agents. Acc. Mater. Res. 2021, 2, 1104–1116. [Google Scholar] [CrossRef]
  59. Chang, T.K.; Cheng, T.M.; Chu, H.L.; Tan, S.H.; Kuo, J.C.; Hsu, P.H.; Su, C.Y.; Chen, H.M.; Lee, C.M.; Kuo, T.R. Metabolic mechanism investigation of antibacterial active cysteine-conjugated gold nanoclusters in Escherichia coli. ACS Sustain. Chem. Eng. 2019, 7, 15479–15486. [Google Scholar] [CrossRef]
  60. Huang, H.; Hwang, G.B.; Wu, G.; Karu, K.; Toit, H.D.; Wu, H.; Callison, J.; Parkin, I.P.; Gavriilidis, A. Rapid synthesis of [Au25 (Cys)18] nanoclusters via carbon monoxide in microfluidic liquid-liquid segmented flow system and their antimicrobial performance. Chem. Eng. J. 2020, 383, 123176. [Google Scholar] [CrossRef]
  61. Chen, Y.; Ren, L.; Sun, L.; Bai, X.; Zhuang, G.; Cao, B.; Hu, G.; Zheng, N.; Liu, S. Amphiphilic silver nanoclusters show active nano-bio interaction with compelling antibacterial activity against multidrug-resistant bacteria. NPG Asia Mater. 2020, 12, 1–15. [Google Scholar] [CrossRef]
  62. Jin, J.; Wu, X.; Xu, J.; Wang, B.; Jiang, F.; Liu, Y. Ultrasmall silver nanoclusters: Highly efficient antibacterial activity and their mechanisms. Biomater. Sci. 2017, 5, 247–257. [Google Scholar] [CrossRef]
  63. Li, Y.; Zhen, J.; Tian, Q.; Shen, C.; Zhang, L.; Yang, K.; Shang, L. One step synthesis of positively charged gold nanoclusters as effective antimicrobial nanoagents against multidrug-resistant bacteria and biofilms. J. Colloid Interface Sci. 2020, 569, 235–243. [Google Scholar] [CrossRef] [PubMed]
  64. Zheng, Y.; Liu, W.; Chen, Y.; Li, C.; Jiang, H.; Wang, X. Conjugating gold nanoclusters and antimicrobial peptides: From aggregation-induced emission to antibacterial synergy. J. Colloid Interface Sci. 2019, 546, 1–10. [Google Scholar] [CrossRef]
  65. Wang, S.; Wang, Y.; Peng, Y.; Yang, X. Exploring the antibacteria performance of multicolor Ag, Au, and Cu nanoclusters. ACS Appl. Mater. Interfaces 2019, 11, 8461–8469. [Google Scholar] [CrossRef]
  66. Zheng, K.; Setyawati, M.I.; Lim, T.P.; Leong, D.T.; Xie, J. Antimicrobial cluster bombs: Silver nanoclusters packed with daptomycin. ACS Nano 2016, 10, 7934–7942. [Google Scholar] [CrossRef] [PubMed]
  67. Ye, Z.; Zhu, H.; Zhang, S.; Li, J.; Wang, J.; Wang, E. Highly efficient nanomedicine from cationic antimicrobial peptide-protected Ag nanoclusters. J. Mater. Chem. B 2021, 9, 307–313. [Google Scholar] [CrossRef] [PubMed]
  68. Xie, Y.; Liu, Y.; Yang, J.; Liu, Y.; Hu, F.; Zhu, K.; Jiang, X. Gold nanoclusters for targeting methicillin-resistant staphylococcus aureus in vivo. Angew. Chem. Int. Ed. 2018, 57, 3958–3962. [Google Scholar] [CrossRef] [PubMed]
  69. Xu, D.; Wang, Q.; Yang, T.; Cao, J.; Lin, Q.; Yuan, Z.; Li, L. Polyethyleneimine capped silver nanoclusters as efficient antibacterial agents. Int. J. Environ. Res. Public Health 2016, 13, 334. [Google Scholar] [CrossRef]
  70. Yang, L.; Yao, C.; Li, F.; Dong, Y.; Zhang, Z.; Yang, D. Synthesis of branched DNA scaffolded super-nanoclusters with enhanced antibacterial performance. Small 2018, 14, 1800185. [Google Scholar] [CrossRef] [PubMed]
  71. Zhu, H.; Li, J.; Wang, J.; Wang, E. Lighting up the gold nanoclusters via host–guest recognition for high-efficiency antibacterial performance and imaging. ACS Appl. Mater. Interfaces 2019, 11, 36831–36838. [Google Scholar] [CrossRef]
  72. Xie, Y.; Zheng, W.; Jiang, X. Near-infrared light-activated phototherapy by gold nanoclusters for dispersing biofilms. ACS Appl. Mater. Interfaces 2020, 12, 9041–9049. [Google Scholar] [CrossRef]
  73. Okamoto, I.; Miyaji, H.; Miyata, S.; Shitomi, K.; Sugaya, T.; Ushijima, N.; Akasaka, T.; Enya, S.; Saita, S.; Kawasaki, H. Antibacterial and antibiofilm photodynamic activities of lysozyme-Au nanoclusters/rose bengal conjugates. ACS Omega 2021, 6, 9279–9290. [Google Scholar] [CrossRef] [PubMed]
  74. Ravindran, G.A.; Balasubramanian, S.; Bright, R.; Cowin, A.J.; Goswami, N.; Vasilev, K. Ultrasmall gold nanocluster based antibacterial nanoaggregates for infectious wound healing. ChemNanoMat 2019, 5, 1176–1181. [Google Scholar] [CrossRef]
  75. Zheng, K.; Li, K.; Chang, T.H.; Xie, J.; Chen, P. Synergistic antimicrobial capability of magnetically oriented graphene oxide conjugated with gold nanoclusters. Adv. Funct. Mater. 2019, 29, 1904603. [Google Scholar] [CrossRef]
  76. Chu, G.; Zhang, C.; Liu, Y.; Cao, Z.; Wang, L.; Chen, Y.; Zhou, W.; Gao, G.; Wang, K.; Cui, D. A gold nanocluster constructed mixed-metal metal-organic network film for combating iImplant-associated infections. ACS Nano 2020, 14, 15633–15645. [Google Scholar] [CrossRef] [PubMed]
  77. Li, K.; Li, D.; Li, C.H.; Zhuang, P.; Dai, C.; Hu, X.; Wang, D.; Liu, Y.; Mei, X.; Rotello, V.M. Efficient in vivo wound healing using noble metal nanoclusters. Nanoscale 2021, 13, 6531–6537. [Google Scholar] [CrossRef] [PubMed]
  78. Wang, Y.; Shen, B.; Zhang, Z.; Chen, Y.; Zhu, L.; Zhang, Y.; Huang, H.; Jiang, L. Multifunctional fluorescent gold nanoclusters with enhanced aggregation-induced emissions (AIEs) and excellent antibacterial effect for bacterial imaging and wound healing. Biomater. Adv. 2022, 137, 212841. [Google Scholar] [CrossRef] [PubMed]
  79. Wang, Y.; Li, C.; Shen, B.; Zhu, L.; Zhang, Y.; Jiang, L. Ultra-small Au/Pt NCs@GOX clusterzyme for enhancing cascade catalytic antibiofilm effect against F. nucleatum-induced periodontitis. Chem. Eng. J. 2023, 466, 143292. [Google Scholar] [CrossRef]
  80. Wu, Z.; Zhao, J.; Xu, R. Recent advances in oral nano-antibiotics for bacterial infection therapy. Int. J. Nanomed. 2020, 15, 9587–9610. [Google Scholar] [CrossRef] [PubMed]
  81. Chen, Z.; Chu, Z.; Jiang, Y.; Xu, L.; Qian, H.; Wang, Y.; Wang, W. Recent advances on nanomaterials for antibacterial treatment of oral diseases. Mater. Today Bio 2023, 20, 100635. [Google Scholar] [CrossRef]
  82. Xie, Y.; Zhang, M.; Zhang, W.; Liu, X.; Zheng, W.; Jiang, X. Gold nanoclusters-coated orthodontic devices can inhibit the formation of Streptococcus mutans biofilm. ACS Biomater. Sci. Eng. 2020, 6, 1239–1246. [Google Scholar] [CrossRef]
  83. Wu, T.; Sun, J.; Lei, J.; Fan, Q.; Tang, X.; Zhu, G.; Yan, Q.; Feng, X.; Shi, B. An efficient treatment of biofilm-induced periodontitis using Pt nanocluster catalysis. Nanoscale 2021, 13, 17912–17919. [Google Scholar] [CrossRef] [PubMed]
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Figure 1. The physicochemical properties, biosafety, and bioactivity of M NCs compared to bulk M NPs.
Figure 1. The physicochemical properties, biosafety, and bioactivity of M NCs compared to bulk M NPs.
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Figure 2. Metal nanocluster bridge between organometallic complexes and plasmonic nanoparticles. Reprinted with permission from [18]. Copyright 2024, American Chemical Society.
Figure 2. Metal nanocluster bridge between organometallic complexes and plasmonic nanoparticles. Reprinted with permission from [18]. Copyright 2024, American Chemical Society.
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Figure 3. The advantages and limitations of major types of M NCs. Reprinted with permission from [38]. Copyright 2024, John Wiley and Sons.
Figure 3. The advantages and limitations of major types of M NCs. Reprinted with permission from [38]. Copyright 2024, John Wiley and Sons.
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Figure 4. Overview of M NC-based bacterial sensing strategies. Reprinted with permission from [42]. Copyright 2024, RSC Pub.
Figure 4. Overview of M NC-based bacterial sensing strategies. Reprinted with permission from [42]. Copyright 2024, RSC Pub.
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Figure 5. (A) HAS-Au NCs as a selective fluorescence probe for the detection of S. aureus and MRSA [45]. (B) Schematic illustration and images of the on–off–on Au NC-based fluorescent probe for rapid E. coli detection [46]. (C) The pH-controllable adherence of GC-Au NCs to E. coli cells [47]. (D) Highly fluorescent Au-Ag NCs recognize A. baumannii with high selectivity and sensitivity [48]. Reprinted with permission from [45,46,47,48]. Copyright 2024, American Chemical Society, John Wiley and Sons, and Elsevier.
Figure 5. (A) HAS-Au NCs as a selective fluorescence probe for the detection of S. aureus and MRSA [45]. (B) Schematic illustration and images of the on–off–on Au NC-based fluorescent probe for rapid E. coli detection [46]. (C) The pH-controllable adherence of GC-Au NCs to E. coli cells [47]. (D) Highly fluorescent Au-Ag NCs recognize A. baumannii with high selectivity and sensitivity [48]. Reprinted with permission from [45,46,47,48]. Copyright 2024, American Chemical Society, John Wiley and Sons, and Elsevier.
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Figure 6. (A) Determination of S. aureus in mixtures using the aptamer–MB and AuNCs@Van dual recognition strategy [50]. (B) Schematic diagram and images of Apt-G enhancing the fluorescence of Nx-Ag NCs [51]. Reprinted with permission from [50,51]. Copyright 2024, American Chemical Society.
Figure 6. (A) Determination of S. aureus in mixtures using the aptamer–MB and AuNCs@Van dual recognition strategy [50]. (B) Schematic diagram and images of Apt-G enhancing the fluorescence of Nx-Ag NCs [51]. Reprinted with permission from [50,51]. Copyright 2024, American Chemical Society.
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Figure 7. Schematic illustration of protein–Au NC-based fluorescence sensor array for discrimination of bacteria. Reprinted with permission from [55]. Copyright 2024, John Wiley and Sons.
Figure 7. Schematic illustration of protein–Au NC-based fluorescence sensor array for discrimination of bacteria. Reprinted with permission from [55]. Copyright 2024, John Wiley and Sons.
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Figure 8. Antibacterial mechanisms of M NCs. Reprinted with permission from [58]. Copyright 2024, American Chemical Society.
Figure 8. Antibacterial mechanisms of M NCs. Reprinted with permission from [58]. Copyright 2024, American Chemical Society.
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Figure 9. (A) Chemical structures of ligands and zeta potentials of Au NCs. (B) Representative photographs of MRSA-infected wound untreated and treated with Au NCs. (C) Corresponding wound sizes (relative area versus initial area). (D) Photographs and bacterial colonies formed on LB-agar plates. Reprinted with permission from [24]. Copyright 2024, American Chemical Society.
Figure 9. (A) Chemical structures of ligands and zeta potentials of Au NCs. (B) Representative photographs of MRSA-infected wound untreated and treated with Au NCs. (C) Corresponding wound sizes (relative area versus initial area). (D) Photographs and bacterial colonies formed on LB-agar plates. Reprinted with permission from [24]. Copyright 2024, American Chemical Society.
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Figure 10. Characterization of biofilm removal effects of various experimental groups. (A) The reduction of biofilm (** p < 0.05 and *** p < 0.01); (B) fluorescence images of biofilm; (C) SEM images of biofilm. Reprinted with permission from [72]. Copyright 2024, American Chemical Society.
Figure 10. Characterization of biofilm removal effects of various experimental groups. (A) The reduction of biofilm (** p < 0.05 and *** p < 0.01); (B) fluorescence images of biofilm; (C) SEM images of biofilm. Reprinted with permission from [72]. Copyright 2024, American Chemical Society.
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Figure 11. Oxidase-like and peroxidase-like properties of CN-Pt NCs and their applications in periodontitis treatment. (A) OXD activities of the CN and CN-Pt NCs in the presence of TMB. (B) POD activities of CN and CN-Pt NCs in the presence of TMB and H2O2. (C) The absorption intensity changes of DPBF treated by CN-Pt NCs with time. (D) Periodontitis model construction and use of the injectable CN-Pt NC ointment. (E) Fuchsin staining for biofilm (green box) recorded by stereomicroscopy. (F) H&E staining for the rats’ periodontal tissue. Reprinted with permission from [83]. Copyright 2024, American Chemical Society.
Figure 11. Oxidase-like and peroxidase-like properties of CN-Pt NCs and their applications in periodontitis treatment. (A) OXD activities of the CN and CN-Pt NCs in the presence of TMB. (B) POD activities of CN and CN-Pt NCs in the presence of TMB and H2O2. (C) The absorption intensity changes of DPBF treated by CN-Pt NCs with time. (D) Periodontitis model construction and use of the injectable CN-Pt NC ointment. (E) Fuchsin staining for biofilm (green box) recorded by stereomicroscopy. (F) H&E staining for the rats’ periodontal tissue. Reprinted with permission from [83]. Copyright 2024, American Chemical Society.
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Table 1. Antibacterial applications and mechanisms of different multifunctional M NCs.
Table 1. Antibacterial applications and mechanisms of different multifunctional M NCs.
SystemLigandFormulationPathogensAntibacterial MechanismRef
M NCs modified with small moleculesCysceinCys-Au NCsE. coliIntracellular ROS[59]
Au25Cys18S. aureusPhotocatalytic generation of ROS[60]
p-Mercaptobenzoic acidAu25 NCs; Au102 NCs; Au144 NCsS. aureusROS; membrane damage; metabolic inactivation[27]
MercaptopyrimidineAuDAMPE. coli, MRSAROS; membrane damage; DNA disruption[24]
Mercaptosuccinic acidAg NCsP. aeruginosa, A. baumannii, E. coliEnzyme-like catalysis; ROS; Ag+ release[61]
Dihydrolipoic acidDHLA-Ag NCsE. coliDestruction of the cell membrane and fluidity; ROS; destruction the cytoplasmic membrane respiratory chain and DNA[62]
MUTABMUTAB-Au NCsB. Subtilis,
S. pneumonia, E.coli		Membrane damage; DNA leakage; ROS[63]
M NCs modified with antibacterial substancesDaptomycinDap-AUDAMP NCsMRSAROS; destruction of the cell membrane and DNA[64]
BacitracinAuNCs@Bacitracin; AgNCs@Bacitracin; CuNCs@BacitracinS. aureusROS; destruction of the cell membrane[65]
DaptomycinAg NCsS. aureusROS; destruction of the cell membrane and DNA[66]
CCLLLLRRRRRR (Dpep)Dpep-Ag NCsE. coli, S.aureusROS; Ag+ release[67]
Quaternary ammonium (QA)QA-Au NCsMRSAROS; destruction of the cell membrane; membrane depolarization[68]
Polyethyleneimine (PEI)PEI-Ag NCsE. coliPEI penetration and sterilization; Ag+ release[69]
M NCs modified with biomacromoleculesDNADNA/Ag NCE. coliAg+[70]
Protamine (Prot)Prot/MTU-Au NCsE. coli, MRSAROS; destruction the cell membrane[71]
DNaseDNase-Au NCsE. coli, S. aureusPhotothermal and photodynamic effect[72]
Nanocluster hybrid systemLysozyme (Lys)Lys-Au NCs/RBS. mutans, E. coli, A. naeslundii, P. gingivalis, P. intermediaROS; destruction of the cell membrane[73]
Mercaptosuccinic acid (MSA)Au NCs/CSE. coli, S. aureusROS; destruction of the cell membrane[74]
6-Mercaptohexanoic acid, cysteamineAu NCs/Ho-GOE. coli, S. aureusPiercing of bacterial membranes; ROS; metabolic inactivation [75]
p-Mercaptobenzoic acidGNCs-based mixed-metal metal−organic network (MM-MON)E. coli, S. aureusDestruction of the cell membrane[76]
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Wang, Y.; Gu, M.; Cheng, J.; Wan, Y.; Zhu, L.; Gao, Z.; Jiang, L. Antibiotic Alternatives: Multifunctional Ultra-Small Metal Nanoclusters for Bacterial Infectious Therapy Application. Molecules 2024, 29, 3117. https://doi.org/10.3390/molecules29133117

AMA Style

Wang Y, Gu M, Cheng J, Wan Y, Zhu L, Gao Z, Jiang L. Antibiotic Alternatives: Multifunctional Ultra-Small Metal Nanoclusters for Bacterial Infectious Therapy Application. Molecules. 2024; 29(13):3117. https://doi.org/10.3390/molecules29133117

Chicago/Turabian Style

Wang, Yuxian, Meng Gu, Jiangyang Cheng, Yusong Wan, Liying Zhu, Zhen Gao, and Ling Jiang. 2024. "Antibiotic Alternatives: Multifunctional Ultra-Small Metal Nanoclusters for Bacterial Infectious Therapy Application" Molecules 29, no. 13: 3117. https://doi.org/10.3390/molecules29133117

APA Style

Wang, Y., Gu, M., Cheng, J., Wan, Y., Zhu, L., Gao, Z., & Jiang, L. (2024). Antibiotic Alternatives: Multifunctional Ultra-Small Metal Nanoclusters for Bacterial Infectious Therapy Application. Molecules, 29(13), 3117. https://doi.org/10.3390/molecules29133117

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