Design, Synthesis, and Bioactivity of Cyclic Lipopeptide Antibiotics with Varied Polarity, Hydrophobicity, and Positive Charge Distribution.

Twenty-three polymyxin analogs with variations at nine amino acid positions were synthesized and assessed for antimicrobial activity and renal cytotoxicity. Compounds , , , and (MIC = 0.125-4 μg/mL) had similar or stronger activities against susceptible and drug-resistant strains of , , , and compared to polymyxin B (MIC = 1-2 μg/mL). Most synthesized compounds (50% cytotoxic concentration, CC ≥ 200 μg/mL) exhibited lower cytotoxicity than polymyxin B (CC = 99 ± 6 μg/mL). Polymyxin S showed high plasma stability and strong efficacy in a mouse systemic infection model (ED = 0.9 mg/kg) against NDM-1-producing , suggesting that it is a potential candidate for drug development. The activity and cytotoxicity results indicated that the amino acids at positions 2, 3, 6, and 7 might be replaced. Effects on activity and cytotoxicity linked to changes in the number of positively charged amino acids varied among different cyclopeptide skeletons, but the underlying mechanisms are unknown.