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

Xianming Zeng,Zhiwen Zhou,Ziyi Zhang,Yunyun Zhou,Shengyu Zhang

doi:10.21577/0103-5053.20210102

Abstract

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.

Highlights

The emergence of clinical drug-resistant strains poses a higher challenge to the treatment of infectious diseases.[1]
The theoretical calculated values for log P (ClogP) were obtained in the present study by using Commercial ChemBioOffice 2010.20 As shown in Table 4, the compounds with low lipophilicity (ClogP ≤ 4.03) (11f, 13a-13e) exhibited good to moderate antibacterial activity against S. aureus, B. subtilis, E. coli and MRSA, which indicated that the introduction of hydrophilic groups like carboxy group and amino group into the steroid skeleton was detrimental to their antibacterial action
Compound 13d, which was the most active one, displayed strong antibacterial activity against S. aureus, B. subtilis, MRSA and E. coli with minimum inhibitory concentration (MIC) values of 1-4 μg mL-1, a broad antibacterial spectrum and low cytotoxicity to human normal cells HEK-293 and L02

Summary

Introduction

The emergence of clinical drug-resistant strains poses a higher challenge to the treatment of infectious diseases.[1]. Compound 13e, which was amino acid derivative, displayed only moderate to mild activity with MICs of 32-64 μg mL-1 against both Gram-positive bacteria and Gram-negative bacteria. Compound 13d, which showed the strongest antibacterial activity, was selected to evaluate the propensity for development of bacterial resistance against both Gram‐positive MRSA and Gram-negative E. coli.

Results

Conclusion