Construction of Antibacterial N‐Halamine Polymer Nanomaterials Capable of Bacterial Membrane Disruption for Efficient Anti‐Infective Wound Therapy

The increasing occurrence of bacterial infection at the wound sites is a serious global problem, demanding the rapid development of new antibacterial materials for wound dressing to avoid the abuse of antibiotics and thereby antibiotic resistance. In this work, the authors first report on antibacterial N‐halamine polymer nanomaterials based on a strategic copolymerization of 3‐allyl‐5,5‐dimethylhydantoin (ADMH) and methyl methacrylate (MMA), which exhibits in vitro and in vivo antimicrobial efficacy against pathogenic bacteria including Staphylococcus aureus and Escherichia coli. Particularly, when a biological evaluation is run for wound therapy, the N‐halamine polymer nanomaterials exhibit a powerful antibacterial efficiency and wound healing ability after a series of histological examination of mouse wound. After the evaluation of biological and chemical surroundings, the proposed four‐stage mechanism suggests that, with unique antibacterial N? Cl bonds, the N‐halamine polymer nanomaterials can disrupt the bacterial membrane, as a result causing intracellular content leaked out and thereby cell death. Based on the synergistic action of antibacterial and wound therapy, the N‐halamine polymer nanomaterials are expected to be promising as wound dressing materials in medical healing and biomaterials.     

Polymer‐Based Surfaces Designed to Reduce Biofilm Formation: From Antimicrobial Polymers to Strategies for Long‐Term Applications

Contact‐active antimicrobial polymer surfaces bear cationic charges and kill or deactivate bacteria by interaction with the negatively charged parts of their cell envelope (lipopolysaccharides, peptidoglycan, and membrane lipids). The exact mechanism of this interaction is still under debate. While cationic antimicrobial polymer surfaces can be very useful for short‐term applications, they lose their activity once they are contaminated by a sufficiently thick layer of adhering biomolecules or bacterial cell debris. This layer shields incoming bacteria from the antimicrobially active cationic surface moieties. Besides discussing antimicrobial surfaces, this feature article focuses on recent strategies that were developed to overcome the contamination problem. This includes bifunctional materials with simultaneously presented antimicrobial and protein‐repellent moieties; polymer surfaces that can be switched from an antimicrobial, cell‐attractive to a cell‐repellent state; polymer surfaces that can be regenerated by enzyme action; degradable antimicrobial polymers; and antimicrobial polymer surfaces with removable top layers.     

Antibacterial Hybrid Hydrogels

Bacterial infectious diseases and bacterial‐infected environments have been threatening the health of human beings all over the world. In view of the increased bacteria resistance caused by overuse or improper use of antibiotics, antibacterial biomaterials are developed as the substitutes for antibiotics in some cases. Among them, antibacterial hydrogels are attracting more and more attention due to easy preparation process and diversity of structures by changing their chemical cross‐linkers via covalent bonds or noncovalent physical interactions, which can endow them with various specific functions such as high toughness and stretchability, injectability, self‐healing, tissue adhesiveness and rapid hemostasis, easy loading and controlled drug release, superior biocompatibility and antioxidation as well as good conductivity. In this review, the recent progress of antibacterial hydrogel including the fabrication methodologies, interior structures, performances, antibacterial mechanisms, and applications of various antibacterial hydrogels is summarized. According to the bacteria‐killing modes of hydrogels, several representative hydrogels such as silver nanoparticles‐based hydrogel, photoresponsive hydrogel including photothermal and photocatalytic, self‐bacteria‐killing hydrogel such as inherent antibacterial peptides and cationic polymers, and antibiotics‐loading hydrogel are focused on. Furthermore, current challenges of antibacterial hydrogels are discussed and future perspectives in this field are also proposed.     

A Trifunctional,Modular Biomaterial Coating: Nonadhesive to Bacteria,Chlorhexidine‐Releasing and Tissue‐Integrating

Various potential anti‐infection strategies can be thought of for biomaterial implants and devices. Permanent, tissue‐integrated implants such as artificial joint prostheses require a different anti‐infection strategy than, for instance, removable urinary catheters. The different requirements set to biomaterials implants and devices in different clinical applications call for tailor‐made strategies. Here, a modular coating‐concept for biomaterials is reported, which in its full, trifunctional form comprises nonadhesiveness to bacteria and antimicrobial release, combined with enhanced tissue integration characteristics. Nonadhesiveness to proteins and bacteria is accomplished by a hydrophilic brush coating (Vitrostealth). The antimicrobial release module is constituted by a chlorhexidine releasing poly(ethylene glycol) diacrylamide based‐coating that continues to release its antimicrobial content also when underneath the nonadhesive top‐coating. The third module, enhancing tissue integration, is realized by the incorporation of the penta‐peptide Glycine‐Arginine‐Glycine‐Aspartic acid‐Serine (GRGDS) within the nonadhesive top‐coating. Modules function in concert or independently of each other. Specifically, tissue integration by the GRGDS‐module does not affect the nonadhesiveness of the Vitrostealth‐module toward bovine serum albumin and Staphylococcus aureus , while the antimicrobial release module does not affect tissue‐integration by the GRGDS‐module. Uniquely, using this modular system, tailor‐made anti‐infection strategies can thus readily be made for biomaterials in different clinical applications.

     

Utilizing Paper‐Based Devices for Antimicrobial‐Resistant Bacteria Detection

Antimicrobial resistance (AMR), the ability of a bacterial species to resist the action of an antimicrobial drug, has been on the rise due to the widespread use of antimicrobial agents. Per the World Health Organization, AMR has an estimated annual cost of USD 34 billion in the US and is predicted to be the number one cause of death worldwide by 2050. One way AMR bacteria can spread, and by which individuals can contract AMR infections, is through contaminated water. Monitoring AMR bacteria in the environment currently requires that samples be transported to a central laboratory for slow and labor intensive tests. We have developed an inexpensive assay using paper‐based analytical devices (PADs) that can test for the presence of β‐lactamase‐mediated resistance. To demonstrate viability, the PAD was used to detect β‐lactam resistance in wastewater and sewage and identified resistance in individual bacterial species isolated from environmental water sources.     

Multimetallic Nanoparticles as Alternative Antimicrobial Agents: Challenges and Perspectives

Recently, infectious diseases caused by bacterial pathogens have become a major cause of morbidity and mortality globally due to their resistance to multiple antibiotics. This has triggered initiatives to develop novel, alternative antimicrobial materials, which solve the issue of infection with multidrug-resistant bacteria. Nanotechnology using nanoscale materials, especially multimetallic nanoparticles (NPs), has attracted interest because of the favorable physicochemical properties of these materials, including antibacterial properties and excellent biocompatibility. Multimetallic NPs, particularly those formed by more than two metals, exhibit rich electronic, optical, and magnetic properties. Multimetallic NP properties, including size and shape, zeta potential, and large surface area, facilitate their efficient interaction with bacterial cell membranes, thereby inducing disruption, reactive oxygen species production, protein dysfunction, DNA damage, and killing potentiated by the host’s immune system. In this review, we summarize research progress on the synergistic effect of multimetallic NPs as alternative antimicrobial agents for treating severe bacterial infections. We highlight recent promising innovations of multimetallic NPs that help overcome antimicrobial resistance. These include insights into their properties, mode of action, the development of synthetic methods, and combinatorial therapies using bi- and trimetallic NPs with other existing antimicrobial agents.     

Vancomycin Resistance Is Overcome by Conjugation of Polycationic Peptides

Multidrug‐resistant bacteria represent one of the biggest challenges facing modern medicine. The increasing prevalence of glycopeptide resistance compromises the efficacy of vancomycin, for a long time considered as the last resort for the treatment of resistant bacteria. To reestablish its activity, polycationic peptides were conjugated to vancomycin. By site‐specific conjugation, derivatives that bear the peptide moiety at four different sites of the antibiotic were synthesized. The most potent compounds exhibited an approximately 1000‐fold increased antimicrobial activity and were able to overcome the most important types of vancomycin resistance. Additional blocking experiments using d ‐Ala‐d ‐Ala revealed a mode of action beyond inhibition of cell‐wall formation. The antimicrobial potential of the lead candidate FU002 for bacterial infection treatments could be demonstrated in an in vivo study. Molecular imaging and biodistribution studies revealed that conjugation engenders superior pharmacokinetics.     

Chloramphenicol collagen sponges for local drug delivery in dentistry

Drug delivery systems based on natural drug carriers have become important due to their non-toxicity and biodegradability. We report here the synthesis and characterization of new biomaterials like sponges containing collagen, chloramphenicol and glutaraldehyde for dentistry. All sponges favour water absorption, showing that increasing the glutaraldehyde content leads to an increase in water uptake. The sponges showed resistance to collagenase degradation and strong activity against the tested bacteria. Kinetic data showed non-Fickian diffusion behaviour with a slow release rate. Taking into account that dental drug delivery systems exhibit low water absorption, slow drug release, high content of drug delivery, good antimicrobial activity, and resistance to enzymatic action, the results obtained in this study indicate the optimal content of glutaraldehyde for the sponge as being 0.5%. The properties of the designed formulations demonstrate that these sponges could be adequate for the treatment and/or the prophylaxis of infected lesions at the dental level.     

Liposomes as Antibiotic Delivery Systems: A Promising Nanotechnological Strategy against Antimicrobial Resistance

Antimicrobial drugs are key tools to prevent and treat bacterial infections. Despite the early success of antibiotics, the current treatment of bacterial infections faces serious challenges due to the emergence and spread of resistant bacteria. Moreover, the decline of research and private investment in new antibiotics further aggravates this antibiotic crisis era. Overcoming the complexity of antimicrobial resistance must go beyond the search of new classes of antibiotics and include the development of alternative solutions. The evolution of nanomedicine has allowed the design of new drug delivery systems with improved therapeutic index for the incorporated compounds. One of the most promising strategies is their association to lipid-based delivery (nano)systems. A drug’s encapsulation in liposomes has been demonstrated to increase its accumulation at the infection site, minimizing drug toxicity and protecting the antibiotic from peripheral degradation. In addition, liposomes may be designed to fuse with bacterial cells, holding the potential to overcome antimicrobial resistance and biofilm formation and constituting a promising solution for the treatment of potential fatal multidrug-resistant bacterial infections, such as methicillin resistant Staphylococcus aureus. In this review, we aim to address the applicability of antibiotic encapsulated liposomes as an effective therapeutic strategy for bacterial infections.     

Bacteria‐Triggered Release of Antimicrobial Agents

Medical devices employed in healthcare practice are often susceptible to microbial contamination. Pathogenic bacteria may attach themselves to device surfaces of catheters or implants by formation of chemically complex biofilms, which may be the direct cause of device failure. Extracellular bacterial lipases are particularly abundant at sites of infection. Herein it is shown how active or proactive compounds attached to polymeric surfaces using lipase‐sensitive linkages, such as fatty acid esters or anhydrides, may be released in response to infection. Proof‐of‐concept of the responsive material is demonstrated by the bacteria‐triggered release of antibiotics to control bacterial populations and signaling molecules to modulate quorum sensing. The self‐regulating system provides the basis for the development of device‐relevant polymeric materials, which only release antibiotics in dependency of the titer of bacteria surrounding the medical device.     

Lethal Effect of Photodynamic Treatment on Persister Bacteria

Persister bacteria tolerate bactericidal antibiotics due to transient and reversible phenotypic changes. As these bacteria can limit the effectiveness of antibiotics to eradicate certain infections, their elimination is a relevant issue. Photodynamic therapy seems suitable for this purpose, but phenotypic tolerance to it has also been reported for Pseudomonas aeruginosa . To test whether any phenotypic feature could confer tolerance against both antibiotics and photoinactivation, survivors from exposures to light in the presence of methylene blue were treated with ofloxacin, an antibiotic effective on nongrowing bacteria. Susceptibility to ofloxacin was normal in these bacteria in spite of their increased ability to survive photodynamic inactivation, suggesting the absence of cross‐tolerance. It thus seemed possible to use one of these treatments to eliminate bacteria which had phenotypic tolerance to the other. To test this strategy, persister bacteria emerging from ofloxacin treatments were submitted to the action of light and methylene blue while the antibiotic remained in the bacterial suspension. Persisters lost their clonogenic ability under these conditions and the effects of the treatments seemed to be synergistic. These observations suggest that photodynamic antimicrobial therapy could be used as a complement to antibiotic treatments to eliminate persister bacteria from localized infections.     

Defect‐Rich Adhesive Nanozymes as Efficient Antibiotics for Enhanced Bacterial Inhibition

Nanozymes have emerged as a new generation of antibiotics with exciting broad‐spectrum antimicrobial properties and negligible biotoxicities. However, their antibacterial efficacies are unsatisfactory due to their inability to trap bacteria and their low catalytic activity. Herein, we report nanozymes with rough surfaces and defect‐rich active edges. The rough surface increases bacterial adhesion and the defect‐rich edges exhibit higher intrinsic peroxidase‐like activity compared to pristine nanozymes due to their lower adsorption energies of H₂O₂ and desorption energy of OH*, as well as the larger exothermic process for the whole reaction. This was demonstrated using drug‐resistant Gram‐negative Escherichia coli and Gram‐positive Staphylococcus aureus in vitro and in vivo. This strategy can be used to engineer nanozymes with enhanced antibacterial function and will pave a new way for the development of alternative antibiotics.     

Synthesis and characterization of amphiphilic antibacterial copolymers

Macromolecule antimicrobials have been explored in foundational research and practical application due to their potential merit for reducing the residual toxicity, increasing their efficiency, selectivity, and prolonging the lifetime of the antimicrobial material. In this work, the quaternized poly(styrene)‐b‐poly(DMAEMA) diblock polymers are synthesized by reversible addition‐fragmentation chain transfer polymerization (RAFT). The minimum inhibitory concentration (MIC) evaluation and optical density (OD) method demonstrated that the amphiphilic antibacterial biomaterials have exceptional antibacterial properties. The amphiphilic polycation has an admirable antibacterial property, and these quaternized diblocks are potent biocides and nonhemolytic. The relationship between the structure and activity is discussed with respect to molecular weight of the diblocks and bacteria structural dependence. Copyright © 2011 John Wiley & Sons, Ltd.     

Nanoarchitectonics in combat against bacterial infection using molecular,interfacial, and material tools

Nanoarchitectonics, as a post-nanotechnology concept, is the methodology for constructing functional materials from nano-units, which bridges the gap between nanotechnology and materials science. The research accomplishes advocating nanoarchitectonics has increased dramatically as overviewed in the initial part of this review. Then, as socially impactful subjects, we exemplify nanoarchitectonics research for bacterial infections according to classifications featured with molecular tools, interfaces, and hierarchically structured materials. In particular, this review article discusses namely three kinds of antibacterial strategies: (i) new antimicrobial agents and therapeutic modalities based on nanoarchitectonics present high bactericidal efficacy against methicillin-resistant Staphylococcus aureus; (ii) antimicrobial nanoarchitectonics structures are integrated into the surface of medical devices to detach or kill approaching bacteria; (iii) the nanoarchitectonics hydrogels act as antimicrobial reservoirs to produce sustained-release antimicrobial agents for long-lasting bacterial killing.     

Halogenated Phenazines that Potently Eradicate Biofilms,MRSA Persister Cells in Non‐Biofilm Cultures,and Mycobacterium tuberculosis

Conventional antibiotics are ineffective against non‐replicating bacteria (for example, bacteria within biofilms). We report a series of halogenated phenazines (HP), inspired by marine antibiotic 1 , that targets persistent bacteria. HP 14 demonstrated the most potent biofilm eradication activities to date against MRSA, MRSE, and VRE biofilms (MBEC=0.2–12.5 μM), as well as the effective killing of MRSA persister cells in non‐biofilm cultures. Frontline MRSA treatments, vancomycin and daptomycin, were unable to eradicate MRSA biofilms or non‐biofilm persisters alongside 14 . HP 13 displayed potent antibacterial activity against slow‐growing M. tuberculosis (MIC=3.13 μM), the leading cause of death by bacterial infection around the world. HP analogues effectively target persistent bacteria through a mechanism that is non‐toxic to mammalian cells and could have a significant impact on treatments for chronic bacterial infections.     

Halogenated Phenazines that Potently Eradicate Biofilms,MRSA Persister Cells in Non‐Biofilm Cultures,and Mycobacterium tuberculosis

Conventional antibiotics are ineffective against non‐replicating bacteria (for example, bacteria within biofilms). We report a series of halogenated phenazines (HP), inspired by marine antibiotic 1 , that targets persistent bacteria. HP 14 demonstrated the most potent biofilm eradication activities to date against MRSA, MRSE, and VRE biofilms (MBEC=0.2–12.5 μM), as well as the effective killing of MRSA persister cells in non‐biofilm cultures. Frontline MRSA treatments, vancomycin and daptomycin, were unable to eradicate MRSA biofilms or non‐biofilm persisters alongside 14 . HP 13 displayed potent antibacterial activity against slow‐growing M. tuberculosis (MIC=3.13 μM), the leading cause of death by bacterial infection around the world. HP analogues effectively target persistent bacteria through a mechanism that is non‐toxic to mammalian cells and could have a significant impact on treatments for chronic bacterial infections.     

Approaches for Mitigating Microbial Biofilm-Related Drug Resistance: A Focus on Micro- and Nanotechnologies

Biofilms play an essential role in chronic and healthcare-associated infections and are more resistant to antimicrobials compared to their planktonic counterparts due to their (1) physiological state, (2) cell density, (3) quorum sensing abilities, (4) presence of extracellular matrix, (5) upregulation of drug efflux pumps, (6) point mutation and overexpression of resistance genes, and (7) presence of persister cells. The genes involved and their implications in antimicrobial resistance are well defined for bacterial biofilms but are understudied in fungal biofilms. Potential therapeutics for biofilm mitigation that have been reported include (1) antimicrobial photodynamic therapy, (2) antimicrobial lock therapy, (3) antimicrobial peptides, (4) electrical methods, and (5) antimicrobial coatings. These approaches exhibit promising characteristics for addressing the impending crisis of antimicrobial resistance (AMR). Recently, advances in the micro- and nanotechnology field have propelled the development of novel biomaterials and approaches to combat biofilms either independently, in combination or as antimicrobial delivery systems. In this review, we will summarize the general principles of clinically important microbial biofilm formation with a focus on fungal biofilms. We will delve into the details of some novel micro- and nanotechnology approaches that have been developed to combat biofilms and the possibility of utilizing them in a clinical setting.     

呼吸内科下呼吸道感染细菌分布及其耐药性分析

目的探析呼吸内科下呼吸道感染细菌分布及其耐药性。方法选择湖北省孝感市中心医院呼吸内科收治1 537例下呼吸道感染患者,行痰液培养明确细菌分布并进行药敏试验掌握抗菌药物耐药情况。结果 1 537例患者共得到672份(43.72%)阳性标本,所获得菌株共782例,其中546例(69.82%)为革兰阴性球菌、157(20.08%)为革兰阳性球菌、79例(10.10%)为真菌。金黄色葡萄球菌、表皮葡萄球菌、肺炎链球菌主要对万古霉素、呋喃妥因、亚胺培南等有较高耐药性。结论革兰阴性球菌为下呼吸道感染最常见病原菌,包括铜绿假单胞菌、鲍式不动杆菌等,耐药分析显示金黄色葡萄球菌、表皮葡萄球菌、肺炎链球菌主要对万古霉素、呋喃妥因、亚胺培南、左氧氟沙星等耐药性高,临床用药时需予以注意。     

pH‐Dependent Coordination of AgI Ions by Histidine: Experiment,Theory, and a Model for SilE

Artificial implants and biomaterials lack the natural defense system of our body and, thus, have to be protected from bacterial adhesion and biofilm formation. In addition to the increasing number of implanted objects, the resistance of bacteria is also an important problem. Silver ions are well‐known for their antimicrobial properties, yet not a lot is known about their mode of action. Silver is expected to interact on many levels, thus the development of silver resistance is very difficult. Nevertheless, some bacteria are able to resist silver, even at higher concentrations. One such defense mechanism of bacteria against heavy‐metal intoxication includes an efflux system. SilE, a periplasmic silver‐binding protein that is involved in this defense mechanism, has been shown to possess numerous histidine functions, which strongly bind to silver atoms, as demonstrated by ourselves previously. Herein, we address the question of how histidine binds to silver ions as a function of pH value. This property is important because the local proton concentration in cells varies. Thus, we solved the crystal structures of histidine–silver complexes at different pH values and also investigated the influence of the amino‐acid configuration. These results were completed by DFT calculations on the binding strength and packing effects and led to the development of a model for the mode of action of SilE.     

Membrane Disruption and Enhanced Inhibition of Cell‐Wall Biosynthesis: A Synergistic Approach to Tackle Vancomycin‐Resistant Bacteria

Resistance to glycopeptide antibiotics, the drugs of choice for life‐threatening bacterial infections, is on the rise. In order to counter the threat of glycopeptide‐resistant bacteria, we report development of a new class of semi‐synthetic glycopeptide antibiotics, which not only target the bacterial membrane but also display enhanced inhibition of cell‐wall biosynthesis through increased binding affinity to their target peptides. The combined effect of these two mechanisms resulted in improved in vitro activity of two to three orders of magnitude over vancomycin and no propensity to trigger drug resistance in bacteria. In murine model of kidney infection, the optimized compound was able to bring bacterial burden down by about 6 logs at 12 mg kg^?1 with no observed toxicity. The results furnished in this report emphasize the potential of this class of compounds as future antibiotics for drug‐resistant Gram‐positive infections.