Antimicrobial Peptide‐Peptoid Macrocycles from the Polymyxin B2 Chemical Space

Macrocycles have emerged as important new modalities in drug discovery. In the context of addressing the global threat of antimicrobial resistance, here we used a genetic algorithm as a computational tool to evolve peptide‐peptoid macrocycles to resemble polymyxin B2 (PMB2), a macrocyclic lipopeptide natural product used as last resort antibiotic. Synthesis and testing of forty‐one PMB2 analogs revealed several peptide‐peptoid macrocycles showing strong, although salt sensitive, activity against Escherichia coli and multidrug‐resistant strains of Pseudomonas aeruginosa, high serum stability and lower toxicity to kidney cells compared to PMB2. These macrocycles resembled PMB2 in terms of outer membrane permeabilization, inner membrane depolarization, lipopolysaccharide binding, and loss of activity when linearized, but unlike PMB2 induced aggregation of intracellular contents, an effect reported for other antimicrobial peptoids. These experiments exemplify a combined computational and experimental approach which might be generally useful to explore the chemical space of macrocyclic peptide natural products.