Antimicrobial peptides in anti-infective and immunomodulatory applications: Mechanisms, challenges, and emerging computational design.

Advancing antimicrobial peptides: Mechanisms, design, and applications in the post-antibiotic era.

The rapid emergence of multidrug-resistant and extensively drug-resistant bacteria has intensified the need for alternative antimicrobial strategies in the post-antibiotic era. Antimicrobial peptides (AMPs), as evolutionarily conserved components of innate immunity, have attracted considerable attention due to their broad-spectrum antimicrobial activity, rapid mechanisms of action, and lower propensity for resistance development. This review summarizes the structural diversity, mechanisms of action, and structure-activity relationships (SAR) of AMPs that underpin their biological activity and guide the rational design of next-generation peptide therapeutics. It further discusses recent advances in peptide engineering, peptidomimetic design, machine learning-assisted discovery, innovative production platforms, and the application of CRISPR-Cas genome editing for production host optimization. In addition, the review highlights synergistic therapeutic strategies, current clinical progress, and the expanding applications of AMPs in medicine, food preservation, agriculture, and aquaculture. Despite these advances, challenges including limited stability, potential toxicity, manufacturing costs, and regulatory barriers continue to hinder widespread clinical translation of AMP-based therapeutics. By integrating recent experimental and computational advances with current translational challenges and future perspectives, this review provides a comprehensive overview of the field and highlights key directions for the rational development and clinical translation of next-generation antimicrobial peptides to combat antimicrobial resistance.

Mechanistic and molecular insights into emerging anti-virulence therapeutics.

Defensins as natural antimicrobial peptide scaffolds against antimicrobial-resistant pathogens: mechanisms, resistance risks, and translational prospects

The growing threat of antimicrobial resistance has increased the need for anti-infective approaches beyond conventional single-target antibiotics. Defensins, a conserved family of cysteine-rich antimicrobial peptides, are promising candidates owing to their structural stability, membrane activity, target-specific mechanisms, immunomodulatory functions, and potential synergy with existing antibiotics. This critical narrative review discusses defensins as potential therapeutics against antimicrobial-resistant pathogens, with a focus on structure-activity relationships, bacterial envelope biology, resistance evolution and cross-resistance, antibiofilm activity, and translational feasibility. Data were synthesized from mammalian, plant, fungal, and insect defensins, together with defensin-derived peptides and defensin mimetics. Unrelated AMPs were included only as contextual comparators and were not treated as defensin-specific evidence. Antibacterial proof-of-concept and translational-readiness evidence were appraised separately, including activity under physiological ionic-strength and serum conditions, protease stability, cytotoxicity, hemolysis, resistance selection, and in vivo efficacy. However, clinical translation has been hampered by inconsistent testing standards, incomplete pharmacokinetic/pharmacodynamic characterization, safety concerns, manufacturing challenges, and inadequate resistance surveillance. Existing evidence does not support classifying defensins as resistance-proof or uniformly less resistance-prone than conventional antibiotics. Instead, they should be regarded as versatile scaffolds whose resistance risk requires candidate-specific evaluation. Future studies should combine standardized broth microdilution with testing in serum, protease-rich environments, and mature biofilms. Candidate progression should require infection-site PK/PD, route-appropriate safety, and efficacy in chronic-wound, device-biofilm, or mucosal-infection models. AI-guided design and delivery systems should advance only when they demonstrably improve stability, exposure, activity, or tolerability, with resistance monitored throughout development and use.

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

Toward microbiota-friendly design and evaluation of antimicrobial peptides: a mini-review.

Dual-Mechanism Antimicrobial Peptides from a Nature-Inspired Scaffold

Antimicrobial peptides are promising alternatives to conventional antibiotics, yet systematic strategies to enhance their potency and elucidate their mechanisms of action remain limited. Here, we generated and evaluated a focused library of 20 peptides derived from the lead peptide L3. Across clinically relevant pathogens, including Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, and Candida albicans, several variants showed enhanced antibacterial activity, reducing MIC values to as low as 32 μg/mL (G2-4). Additional candidates (G1-8, G2-1, G2-2, G2-10) achieved MICs of 64 μg/mL against E. coli. Studies in environmental Escherichia isolates revealed species-specific susceptibility patterns. Mechanistic investigations demonstrated minimal membrane-lytic activity at concentrations exceeding their MICs, indicating that membrane disruption is not their primary mode of action. In contrast, in vitro transcription/translation assays demonstrated potent inhibition of protein expression. These results demonstrate how targeted sequence refinement can substantially enhance antimicrobial potency while modulating interactions with bacterial membranes and the transcription/translation machinery.