Probiotic-Derived Antimicrobial Proteins and Peptides: Molecular Mechanisms, Clinical Applications, and Future Therapeutic Perspectives.

Increased antimicrobial resistance and the shortage of new drugs in the pipeline are driving interest in alternative approaches to treating infectious diseases. Probiotic microorganisms, particularly lactic acid bacteria, produce a variety of antimicrobial proteins and peptides (PAPs), such as bacteriocins and caseinolytic fragments, that act in ways distinct from conventional antimicrobials. This review aimed to synthesise the current evidence on PAP mechanisms, host-modulatory effects, and translational perspectives. PAPs have four distinct direct antimicrobial mechanisms: disruption of the bacterial cell wall, inhibition of cell-wall biosynthesis, disruption of intracellular targets (nucleic acids, ribosomes and metabolic pathways), and inhibition of virulence associated with biofilm and quorum sensing. These direct effects can be augmented by synergistic interactions with conventional antibiotics, and by host-modulatory effects related to epithelial barrier function and immune-signalling. Their antimicrobial action is not only direct but also involves upregulation of epithelial barrier function and modulation of immune signalling (NF-κB, MAPK, and inflammasome pathways), as they are dual antimicrobial-immunomodulatory agents. These range from gastrointestinal, respiratory, and urogenital infections to food preservation and the management of multidrug-resistant pathogens. There are still limitations to peptide translation, including stability, scalability, safety, and regulatory classification. Solutions in the early stages of development, such as engineered peptides, synthetic biology delivery platforms, AI-powered discovery, precision probiotics, and combinations of antibiotics and probiotics, present exciting avenues for clinical deployment.