From Environmental Toxicants to Antibacterial Agents:BPA Analogues Selectively Inhibit the Growth of Gram-Positive Bacteria by Disturbing Biosynthesis of the Cell Wall

作     者：Huiming Cao Zhunjie Li Bolei Chen Jing Wang Zhen Zhou Zhi Li Yun Qian Yong Liang 

作者机构：Hubei Key Laboratory of Environmental and Health Effects of Persistent Toxic SubstancesSchool of Environment and HealthJianghan UniversityWuhan 430056P.R.China Department of OrthopedicsGeneral Hospital of Central Theater Command of Chinese People’s Liberation ArmyWuhan 430070P.R.China Department of Biomedical EngineeringFlorida International UniversityMiamiFlorida 33174United States 

出 版 物：《Environment & Health》 (环境与健康（英文）)

年 卷 期：2023年第1卷第4期

页      面：291-299页

学科分类：081704[工学-应用化学] 07[理学] 08[工学] 0817[工学-化学工程与技术] 070303[理学-有机化学] 0703[理学-化学] 

基　　金：supported by grants from the National Key Research and Development Program of China(2020YFA0907500) the National Natural Science Foundation of China(22193051,21277062,21806058) the Excellent Discipline Cultivation Project by JHUN(2023XKZ029) the PLA Logistics Research Project of China(2023) 

主　　题：Environmental toxicants Antibacterial agents BPA analogues Lipoteichoic acid Virtual screening Machine learning 

摘      要：Remarkable antibacterial activity of BPA analogues especially for tetrabromobi-sphenol A against Staphylococcus aureus 25923(Sa25923)and methicillin-resistant Staphylococcus aureus(MRSA)has been reported in our previous ***,the toxic effects of the compounds as environmental contaminants on the endocrine system limited their applications in the field of medicine and *** the abuse of antibiotics has led to the emergence of multiple super-resistant bacteria,we considered that structural modifications based on the BPA structure will be available for molecular designing of potential antimicrobial agents without drug *** this study,to further improve the antibacterial activity and reduce the biological toxicity,we performed the computational models to evaluate the binding affinities of BPA analogues to the potential target DltA protein in the biosynthesis of cell wall.A series of synthesized achiral analogues ofα,α,α′-tris(4-hydroxyphenyl)-1-ethyl-4-isopropylbenzene(α,α,α′-TEIB)exhibited low minimum inhibitory concentration against Sa25923 and MRSA(2 or 1μg mL−1).Especially,the analogue A4 did not induce the drug-resistant mutants for all tested Gram-positive bacterial strains and exhibited relatively lower cytotoxicity in HepG2 *** developed classification model based on the light gradient boosting algorithm showed the superior performances on the internal robustness and generalization ability for the ligand-based virtual screening of bisphenol and polyphenol antimicrobial ***,our findings suggest that the molecular structure ofα,α,α′-TEIB is promising as a scaffold,which is expected to achieve a breakthrough in the development of antibiotics which can prevent the invasion of MRSA and other super bacteria.