期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2117283119
关键词
defensins; peptidomimetic antibiotics; antimicrobial resistance; infections
资金
- Zhejiang University special scientific research fund for COVID-19 prevention and control [2020XGZX100]
- National Natural Science Foundation of China [82030062]
A new class of peptidomimetic antibiotics designed based on the structure of human alpha-defensin 5 (HD5) showed promising activity against drug-resistant bacteria through multiple mechanisms of action.
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 alpha-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.
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