Discovery of novel Thymol-TPP antibiotics that eradicate MRSA persisters

Discovery of novel Thymol-TPP antibiotics that eradicate MRSA persisters

European Journal of Medicinal Chemistry

10.1016/j.ejmech.2024.116381

https://doi.org/10.1016/j.ejmech.2024.116381

Ziyi Tang, Jizhou Feng, Mahesh Challa, Sankara Rao Rowthu, Shuxin Xiong, Cheng Zou, Jianguo Li, Chandra Shekhar Verma, Haibo Peng, Xiaoli He, Chao Huang, Yun He

Antibacterial

03 April 2024

Tang, Z., Feng, J., Challa, M., Rowthu, S. R., Xiong, S., Zou, C., Li, J., Verma, C. S., Peng, H., He, X., Huang, C., & He, Y. (2024). Discovery of novel Thymol-TPP antibiotics that eradicate MRSA persisters. European Journal of Medicinal Chemistry, 270, 116381. https://doi.org/10.1016/j.ejmech.2024.116381

The high prevalence of methicillin-resistant Staphylococcus aureus (MRSA) strains and the formation of non-growing, 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.

Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)

This research / project is supported by the National Natural Science Foundation of China - NA
Grant Reference no. : 22071012

This research / project is supported by the Chongqing Postdoctoral Science Foundation - NA
Grant Reference no. : cstc2021jcyj-bshX0081

This research / project is supported by the Agency for Science, Technology and Research - Career Development Award
Grant Reference no. : 202D8155

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