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 M 2 , 14, S 2 , and 16 (MIC = 0.125–4 μg/mL) had similar or stronger activities against susceptible and drug-resistant strains of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii compared to polymyxin B (MIC = 1–2 μg/mL). Most synthesized compounds (50% cytotoxic concentration, CC50 ≥ 200 μg/mL) exhibited lower cytotoxicity than polymyxin B (CC50 = 99 ± 6 μg/mL). Polymyxin S2 showed high plasma stability in vitro and strong efficacy in a mouse systemic infection model (ED50 = 0.9 mg/kg) against NDM-1-producing Klebsiella pneumoniae, 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.