Journal Article

Human defensin-inspired discovery of peptidomimetic antibiotics

Luo, Gan, Ganz, Tomas, Lu, WuYuan, Xu, ZhiPeng, Zhang, Jue, Nemeth, Elizabeta, Fang, Xiang Ming, Wang, HanBin, Sun, YaQi, Li, Hui, Zhang, Yan, Cheng, BaoLi

2022

Overview

Antibiotics with multiple mechanisms of action and broad-spectrum are urgently required to combat the growing health threat posed by resistant pathogenic microorganisms. Combining computational and medicinal chemistry tools, we used the structure of human α-defensin 5 (HD5) to design a class of peptidomimetic antibiotics with improved activity against both gram-negative and gram-positive bacteria. The most promising lead, compound 10, showed potent killing of multiple drug-resistant gram-negative bacteria isolated from patients. Compound 10 exhibited a multiplex mechanism of action through targeting membrane components—outer membrane protein A and lipopolysaccharide, as well as a potential intracellular target—70S ribosome, thus causing membrane perturbation and inhibition of protein synthesis. In vivo efficacy, stability, and safety of compound 10 were also validated. This human defensin-inspired synthetic peptidomimetic could help solve the serious problem of drug resistance to conventional antibiotics.

• Publisher: National Academy of Sciences
• Subject: Anti-Bacterial Agents - chemistry / Anti-Bacterial Agents - pharmacology / Antibiotics / Bacteria / Biological Sciences / Computer applications / Defensins - chemistry / Defensins - pharmacology / Drug Discovery - methods / Drug resistance / Gram-negative bacteria / Gram-Negative Bacteria - drug effects / Gram-positive bacteria / Health risks / Humans / Lipopolysaccharides / Medical Sciences / Membrane proteins / Membranes / Microbial Sensitivity Tests / Microorganisms / Molecular Structure / Multidrug resistance / Peptidomimetics - chemistry / Peptidomimetics - pharmacology / Perturbation / Protein A / Protein biosynthesis / Protein synthesis / Proteins / Software / Structure-Activity Relationship