Membrane-Active Nonivamide Derivatives as Effective Broad-Spectrum Antimicrobials: Rational Design, Synthesis, and Biological Evaluation

Antibiotic resistance is emerging as a “global public health concern”. To address the growing epidemic of multidrug-resistant pathogens, the development of novel antimicrobials is urgently needed. In this study, by biomimicking cationic antibacterial peptides, we designed and synthesized a series of new membrane-active nonivamide and capsaicin derivatives as peptidomimetic antimicrobials. Through modulating charge/hydrophobicity balance and rationalizing structure–activity relationships of these peptidomimetics, compound 51 was identified as the lead compound. Compound 51 exhibited potent antibacterial activity against both Gram-positive bacteria (MICs = 0.39–0.78 μg/mL) and Gram-negative bacteria (MICs = 1.56–6.25 μg/mL), with low hemolytic activity and low cytotoxicity. Compound 51 displayed a faster bactericidal action through a membrane-disruptive mechanism and avoided bacterial resistance development. Furthermore, compound 51 significantly reduced the microbial burden in a murine model of keratitis infected by Staphylococcus aureus or Pseudomonas aeruginosa. Hence, this design strategy can provide a promising and effective solution to overcome antibiotic resistance.