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Discovery of novel Thymol-TPP antibiotics that eradicate MRSA persisters
Tang, Ziyi1; Feng, Jizhou2; Challa, Mahesh2; Rowthu, Sankara Rao2; Xiong, Shuxin2; Zou, Cheng2; Li, Jianguo3,4; Verma, Chandra Shekhar4,5,6; Peng, Haibo7; He, Xiaoli1
2024-04-15
摘要The high prevalence of methicillin-resistant Staphylococcus aureus (MRSA) strains and the formation of nongrowing, dormant "persisters" subsets help bacteria evade antibiotic treatment and enhance bacterial resistance, which poses a serious threat to human life and health. It is urgent to discover novel antibacterial therapies effective against MRSA persisters. Thymol is a common nutraceutical with weak antibacterial and antitumor activities. A series of Thymol triphenylphosphine (TPP) conjugates ( TPP-Thy3 ) was designed and synthesized. These compounds showed significantly improved inhibitory activity against Gram-positive bacteria compared with Thymol. Among them, Thy3d displayed a low probability of resistance selection and showed excellent biocompatibility. Interestingly, Thy3d elicited a rapid killing effect of MRSA persisters (99.999%) at high concentration. Fluorescence experiments, electron microscopy, molecular dynamics simulation and bilayer experiment confirmed that Thy3d conjugates exerted potent antimicrobial activity by disrupting the integrity of the membrane of bacterial even the persister. Furthermore, Thy3d exhibited considerable efficacy in a mouse model of subcutaneous murine MRSA infection. In summary, TPP-Thy3 conjugates are a series of novel antibacterial agents and could serve as a new therapeutic strategy for combating antibiotic resistance.
关键词Antibacterial Thymol Triphenylphosphonium (TPP)-conjugates Persister
DOI10.1016/j.ejmech.2024.116381
发表期刊EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ISSN0223-5234
卷号270页码:15
通讯作者Huang, Chao(chuang@cqu.edu.cn) ; He, Yun(yun.he@cqu.edu.cn)
收录类别SCI
WOS记录号WOS:001227149900003
语种英语