Peptide antimicrobials: cell wall as a bacterial target

Endogenous host defense peptides (HDPs) are among the most ancient immune mediators, constituting a first line of defense against invading pathogens across the evolutionary continuum. Generally, HDPs are small (<10 kDa), cationic, and amphipathic polypeptides, often broadly classified based on structure. In eukaryotes, major HDP classes include disulfide-stabilized (e.g., defensins), and α-helical or extended (e.g., cathelicidins) peptides. Prokaryote HDPs are generally referred to as bacteriocins, colicins, or lantibiotics, many of which undergo extensive posttranslational modifications. One target for prokaryotic and eukaryotic HDPs is the bacterial cell wall, an essential structural feature conserved among broad classes of bacteria. A primary building block of the cell wall is peptidoglycan, a macromolecular complex that arises through a series of reactions including membrane translocation, extracellular anchoring, and side chain cross-linking. Each of these steps represents a potential target for HDP inhibition, leading to bacteriostatic or bactericidal outcomes. Thus, understanding the relationships between HDPs and cell wall targets may shed light on new peptide antimicrobial agents and strategies to meet the daunting challenge of antibiotic resistance.