A Smart Polypeptide-Based Photoresponsive Nanotherapeutic against Methicillin-Resistant Staphylococcus aureus.

Quaternary Ammonium-Functionalized Membrane-Anchored Photosensitizer against Multidrug-Resistant Bacterial Infections.

The discovery of new antimicrobial medications has not kept up with the evolution of bacterial resistance, and infections with drug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), continue to pose a serious threat to global public health. Antimicrobial photodynamic therapy (aPDT), as an alternative strategy, produces reactive oxygen species (ROS) under light activation and kills drug-resistant bacteria through oxidative damage. Nevertheless, conventional photosensitizers (PSs) are limited by aggregation-caused quenching, inadequate bacterial selectivity, and off-target cytotoxicity. Quaternary ammonium salts (QASs) can preferentially accumulate on bacterial membranes through electrostatic interactions and disrupt the bacterial membranes. The quaternary ammonium PS PK4, reported here has a triphenylamine unit that enhances ROS production. Under white light irradiation, PK4 produces abundant ROS that oxidatively damage bacterial membranes, while exhibiting high photostability and minimal dark toxicity. In an MRSA-infected wound model, PK4-mediated phototherapy can reduce inflammation, accelerate wound healing, and enhance collagen deposition without systemic toxicity, providing a promising aPDT strategy for combating drug-resistant bacterial infections.

Glycan-decorated polymeric nanomedicine for the treatment of multidrug-resistant infections

The antimicrobial resistance (AMR) crisis necessitates strategies to revitalize existing antibiotics against multidrug-resistant pathogens. While cationic antimicrobial polymers can disrupt bacterial membranes, their clinical translation is hindered by host toxicity. Here we report a hierarchical, stimuli-responsive nanomedicine designed on principles of safety, specificity, switchability, and synergy. We synthesized phenylboronic ester-caged biodegradable polymers shielded by functional polysaccharide shells. These nanoparticles remain inert during circulation but selectively activate within infection microenvironments. Upon activation, the exposed cationic polymer physically compromises bacterial membranes, enabling the entry of co-delivered antibiotics such as rifampicin into Gram-positive, Gram-negative, mycobacterial, and biofilm-embedded pathogens. Our research led to the discovery of glycans that significantly improve therapeutic outcomes. We found that different glycans exhibited distinct effects in various tissues and conditions: chondroitin sulfate effectively targeted CD44-abundant infectious niches, enabling precise localization and enhanced therapeutic efficacy, whereas levan uniquely stimulated macrophage oxidative bursts, promoting intracellular pathogen clearance. By leveraging these distinct biological interactions, our platform overcomes the physical and biological barriers of AMR, offering a universal strategy to treat diverse, multidrug-resistant infections.

Antibacterial peptide nanofibrils for targeted elimination of drug-resistant Staphylococci.

Antibacterial resistance represents a major global health challenge, particularly due to drug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), which is known for causing persistent, biofilm-associated infections. In this study, we introduce self-assembling, tryptophan-rich peptide nanofibrils derived from DVFLGREEWWWWC (D4W) as potent antibacterial agents against Staphylococcus species, including MRSA. These self-assembling D4W units form amyloid fibril-like structures through controlled polarity reversal, enhancing their structural stability and antibacterial efficacy. The DVFLG motif enables selective recognition of Staphylococci, while the WWWW segment facilitates β-sheet formation and deep membrane penetration via hydrophobic interactions, effectively disrupting bacterial membranes. Moreover, D4W-derived nanofibrils engage in multivalent interactions with bacterial surfaces, significantly enhancing targeting precision and antibacterial efficacy. Beyond eradicating planktonic Staphylococci, D4W-derived nanofibrils significantly inhibit biofilm formation, a main factor in antibiotic resistance. Notably, D4W-derived nanofibrils exhibit low cytotoxicity and hemotoxicity, addressing their therapeutic potential. Their efficacy was validated in ex vivo pig skin and in vivo zebrafish embryo models, where they successfully inhibited MRSA growth. In addition, molecular dynamics simulations were employed to elucidate the interactions between D4W and model lipid membranes. This study introduces a strategy for designing effective antibacterial agents with enhanced stability, selectivity, and biofilm-prevention capabilities against drug-resistant Staphylococci. Our results indicate the promise of self-assembling peptide-based therapeutics in combating antibiotic-resistant Staphylococcal infections.

Antibacterial photoswitchable triazenic ciprofloxacins.

Dendrimers as Multi-Target Nanotherapeutic Strategies Against Antimicrobial Resistance: Current Drug Targets and Mechanistic Insights

Antibiotics are also regarded as transformative therapeutic agents that are rapidly losing their clinical effectiveness because of the global escalation of antimicrobial resistance (AMR). Irrational and extensive antibiotic use has accelerated the emergence of resistant pathogens through mechanisms such as low membrane permeability, target modification, active efflux, quorum–sensing–regulated virulence, and biofilm formation, which leads to increased morbidity and mortality worldwide. This urgent crisis needs innovative, target-based therapeutic techniques beyond conventional antibiotics. In this context, dendrimers, synthetic, highly branched nanostructures with well-defined architecture and tunable surface functionality, have come as promising multi-target antimicrobial systems. Dendrimers directly disrupt bacterial cell membranes, which enhances permeability and promotes antibiotic penetration while simultaneously interacting with critical resistance determinants, including penicillin-binding proteins (PBPs), quorum sensing (QS) pathways, which are involved in virulence and biofilm regulation, and efflux pumps responsible for drug expulsion. Multiple dendrimer classes, which include poly (amid amine) (PAMAM), polypropylene imine (PPI), carbosilane, and peptide dendrimers, have shown intrinsic antimicrobial activity and strong synergistic effects with conventional antibiotics. Their internal cavities enable efficient drug encapsulation, and surface modifications allow targeted delivery, improved pharmacokinetics, and enhanced activity against both planktonic bacteria and biofilms. These properties allow dendrimers to overcome multiple bacterial resistance mechanisms simultaneously. This review gives a focus on the antimicrobial mechanisms, dendrimer design parameters, and pharmaceutical approaches that allow them to be translated into next-generation anti-infective treatments

Cyclic dipeptide-based antimicrobials with potent antibacterial activity.

The spread of antibiotic resistance has become a major challenge in global public health, and there is an urgent need to develop novel antibacterial agents with low resistance. Peptide-based antibacterial agents have attracted increasing attention for their membrane-targeting mechanisms, which may reduce the risk of the development of resistance. Herein, a series of quaternary ammonium-modified cyclic dipeptides (named cHHn-m) were designed and synthesized through a quaternization reaction and their antibacterial activity and cytotoxicity were systematically investigated. The optimal cyclic dipeptides (cHH8-6) demonstrated the best antibacterial ability with MIC values of 2.0 and 3.9 μg mL-1 against S. aureus and E. coli, respectively. Antibacterial mechanism studies indicate that cHH8-6 can bind to a negatively charged bacterial membrane through electrostatic interactions, subsequently disrupting the integrity of the bacterial membrane. Due to its unique mechanism, cHH8-6 is less likely to induce bacterial resistance compared to clinical antibiotics. In addition, cHH8-6 effectively inhibited bacterial biofilm formation and eradicated mature bacterial biofilms. In bacterial-induced mouse models of epidermal and keratitis infections, cHH8-6 effectively reduces the bacterial count at the infection site with negligible in vivo toxicity. This study provides a novel approach for treating clinical bacterial infections.