Antimicrobial peptides: natural templates for next-generation therapeutics against antimicrobial resistance

Abstract

Antimicrobial resistance is a growing global health crisis, responsible for nearly five million deaths annually and projected to double by 2050 as conventional antibiotics fail against multidrug-resistant pathogens. AMR is aggravated by antibiotic misuse, weak regulations, inadequate prevention, high treatment costs, and the limited discovery of new antimicrobials. In this context, antimicrobial peptides, including natural, synthetic, and computationally designed variants, have emerged as promising alternatives. AMPs display broad-spectrum antibacterial, antifungal, antiviral, antiparasitic, antibiofilm, and immunomodulatory activities, with a lower tendency to induce resistance. Their mechanisms include membrane disruption, intracellular targeting, immune modulation, and selective binding to negatively charged microbial membranes. Structural features such as α-helices, β-sheets, cyclic motifs, and post-translational modifications enhance potency and specificity. Recent advances in chemical modification, recombinant expression systems, nanotechnology, and AI-driven computational approaches have improved AMP stability, bioavailability, and therapeutic efficacy. Synthetic derivatives like innate defense regulators and conjugated AMPs further enhance immunomodulatory properties and reduce toxicity, while combination therapies increase effectiveness. Challenges remain, including degradation, short half-life, production costs, and microbial defenses such as biofilms and efflux pumps. Nevertheless, high-throughput sequencing and screening, structural biology, and structure–activity relationship studies continue to accelerate AMP development, positioning them as vital next-generation therapeutics against AMR.