Broad Spectrum Antibacterial Ocotillol-Type Derivatives: Semi-Synthesis, Structure-Activity Relationship, and Membrane-Active Mode of Action

A series of 3-amino substituted ocotillol-type derivatives were designed and synthesized for the first time. The in vitro antibacterial activity tests showed that some of the new compounds exhibited excellent antibacterial activity. Compound 13d, which was the most active one, displayed particularly strong antibacterial activity against S. aureus, B. subtilis, MRSA (methicillin-resistant S. aureus) and E. coli with minimum inhibitory concentration (MIC) values of 1-4 μg mL-1. Further research also suggested that 13d showed low cytotoxicity to human normal cells HEK-293 and L02, strong synergistic effects with kanamycin or chloramphenicol and a broad antibacterial spectrum including against multidrug-resistant strains. This active molecule 13d also induced bacterial resistance more slowly than norfloxacin and colistin. Furthermore, the research results demonstrated that this type of compounds could disperse the established bacterial biofilms, thus suppressing or delaying the development of drug resistance. Mechanism studies have shown that compound 13d could damage the integrity of cell membranes, which in turn facilitated the antibacterial agents binding to deoxyribonucleic acid (DNA), leading to cell death. Therefore, these results indicated that the membrane active ocotillol-type derivatives are a promising class of antibacterial agents to fight against super bacteria and deserve further attention.