Animal-Derived Antimicrobial Peptides: Emerging Therapeutic Strategies against Multidrug-Resistant Pathogens

The global escalation of antimicrobial resistance (AMR) has outpaced the conventional antibiotic discovery pipeline, with bacterial AMR associated with an estimated 4.71 million deaths in 2021 and forecast to contribute to rising mortality through 2050. The World Health Organization's 2024 Bacterial Priority Pathogens List continues to identify carbapenem-resistant Gram-negative organisms and rifampicin-resistant Mycobacterium tuberculosis as the most urgent targets for new therapeutics. Antimicrobial peptides (AMPs), ancient and evolutionarily conserved effectors of innate immunity, are one of several candidate classes under active investigation. The animal kingdom, spanning mammals, amphibians, fish, insects, arachnids, and venomous taxa, is a structurally and functionally diverse reservoir of these molecules, and this diversity has already attracted several recent, more narrowly focused reviews covering venom-derived, marine-derived, and computationally designed AMPs. The present narrative review instead undertakes a cross-taxon comparative synthesis, explicitly distinguishing native animal peptides, proteolytic fragments of animal proteins, and synthetic analogues derived from an animal scaffold from the bacterial and fungal peptide antibiotics sometimes discussed alongside them. We survey the principal structural families and their taxonomic sources, compare their membrane-disruptive and intracellular mechanisms, and critically assess their anti-biofilm activity by distinguishing biofilm prevention from eradication of established biofilms. We examine the molecular determinants of bacterial resistance to AMPs with reference to the primary mechanistic literature, and we compile a verified, trial-identifier-referenced account of clinical development that separates candidates with completed Phase III evaluation from those with only preclinical or unverified clinical support. Every animal-derived AMP evaluated in a controlled human trial to date has either failed to demonstrate superiority over an existing comparator or remains restricted to topical or localised use; none has achieved new systemic regulatory approval. Against this evidence base, we argue that the realistic near-term contribution of animal-derived AMPs lies in combination therapy with existing antibiotics and in topical or localised indications with direct clinical evidence, while their use as stand-alone systemic agents remains a preclinical and early-clinical prospect rather than an established therapeutic reality.