Development of amphipathic derivatives of thymol and carvacrol as potent broad-spectrum antibacterial agents

In the current study, to discover novel Antibacterial agents, we designed and synthesized 72 carvacrol and thymol derivatives by biomimicking the structure and function of cationic Antimicrobial Peptides (AMPs). Many of the derivatives showed good Antibacterial activity, and compound thy2I exhibited the most potent Antibacterial activity with minimum inhibitory concentration (MIC) values ranging from 0.5 μg/mL to 8 μg/mL. Compound thy2I could kill both gram-positive and gram-negative bacteria via a membrane-targeting mechanism of action with a low frequency of resistance. In addition, thy2I had the advantages of good membrane selectivity, low toxicity in vitro and in vivo, and good plasma stability. The in vivo activity results revealed that thy2I exhibited a positive therapeutic effect in a mouse skin abscess model induced by Staphylococcus aureus ATCC29213. After thy2I treatment (10 mg/kg), the Bacterial load of the S. aureus-infected abscesses was reduced by approximately 99.65 %. Our study suggests that thy2I may serve as an Antibacterial lead for further clinical evaluation.

Amphipathic conjugates; Antibacterial activity; Carvacrol; Thymol.