Antimicrobial Peptides (AMPs) represent one of the most durable and effective defence of multicellular organisms against bacterial infections. These cationic and amphipathic peptides represent promising leads for the development of antibiotics combatting the resistance of bacteria against antibiotics. However, their clinical applications have often been limited by an inadequate margin of safety .
A prodrug approach can overcome a toxicity barrier in drug delivery. Prodrugs of AMPs can be generated by transiently reducing or annulling their net positive charges by attaching a negative promoiety through a linker which can be degraded by an enzyme (bacterial or human) confined to sites of infection. For example, neutrophil elastase (NE), a human protease involved in chronic airway inflammation and infections associated with cystic fibrosis (CF), can restore the cationic property of AMPs modified with oligo-glutamate promoieties. Consequently, their bactericidal activities against the CF pathogen P. aeruginosa are restored by NE in CF bronchoalveolar lavage fluids. The potential of this prodrug approach in reducing the safety barrier in the clinical use of AMPs has also been demonstrated in vivo, in a murine model of lung delivery .
In parallel, a novel class of peptidomimetics with antimicrobial activities similar to AMPs, against Gram-positive bacteria, has been developed. Their spectrum of activity is currently extended to Gram-negative organisms.
 Zasloff M. Antimicrobial peptides of multicellular organisms. Nature. 2002, 415(6870):389-395.
 Forde É, Schütte A, Reeves E, Greene C, Humphreys H, Mall M, Fitzgerald-Hughes D, Devocelle M. Differential In Vitro and In Vivo Toxicities of Antimicrobial Peptide Prodrugs for Potential Use in Cystic Fibrosis. Antimicrob Agents Chemother. 2016, 60(5):2813-2821.