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 mu g/mL) and Gram-negative bacteria (MICs = 1.56- 6.25 mu g/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.

Automated summary

Antibiotic resistance is a global public health concern, and the development of novel antimicrobials is urgently needed. In this study, a series of new peptidomimetic antimicrobials were designed and synthesized, with compound 51 identified as the lead compound due to its potent antibacterial activity, low toxicity, and avoidance of bacterial resistance development. Compound 51 also significantly reduced microbial burden in a murine model of keratitis infected by Staphylococcus aureus or Pseudomonas aeruginosa. This design strategy provides a promising and effective solution to overcome antibiotic resistance.