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Topic Overview:

The rising prevalence of antibiotic resistance underscores the urgent need for novel antimicrobial agents. Antimicrobial peptides (AMPs) are potentially effective therapeutics that disrupt bacterial membranes regardless of resistance to traditional antibiotics. Deslouches and colleagues have developed engineered cationic AMPs (eCAPs) with broad activity against multidrug-resistant (MDR) bacteria to overcome major challenges to clinical development, including the tendency to increase host toxicity when optimizing for high antimicrobial potency. Therefore, Deslouches and colleagues have established a rational framework using a series of rationally engineered libraries of novel peptide antibiotics (PAX) to establish the distinction between structural determinants of antimicrobial potency and those of host toxicity. Each PAX library begins with a short template made of 4 Arg and 4 Trp residues. The cationic amphipathic structure was effectively dissected by the stepwise addition of 1 Arg and 1 Val at a time to reach a maximum length of 24 residues. Further positional variation of the Trp residues resulted in multiple libraries of a maximum of 83 peptides (in addition to controls), which demonstrated accurate correlation of antibacterial activity with length, charge, and hydrophobicity within each library. As predicted, lowest mean minimum inhibitory concentrations (MIC) are achieved against MDR clinical isolates without substantial increase in red blood cell lysis or toxicity to white blood cells at maximum test concentrations. As proof of concept, one of the selected PAX (E35) demonstrates efficacy at a systemic dose of 4-5mg/kg in an MDR P. aeruginosa mouse model with a maximum tolerated dose of 30mg/kg. The data indicate that the rational framework can be applied to PAX with different amino acid composition to achieve safety and optimal efficacy. These studies will set the stage for advanced preclinical development.