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 

机构地区：[1]Hubei Key Laboratory of Environmental and Health Effects of Persistent Toxic Substances,School of Environment and Health,Jianghan University,Wuhan 430056,P.R.China [2]Department of Orthopedics,General Hospital of Central Theater Command of Chinese People’s Liberation Army,Wuhan 430070,P.R.China [3]Department of Biomedical Engineering,Florida International University,Miami,Florida 33174,United States

出　　处：《Environment & Health》2023年第4期291-299,共9页环境与健康（英文）

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).

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 studies.However,the toxic effects of the compounds as environmental contaminants on the endocrine system limited their applications in the field of medicine and health.Given 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 resistance.In 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 cells.The 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 substances.Collectively,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.

关 键 词：Environmental toxicants Antibacterial agents BPA analogues Lipoteichoic acid Virtual screening Machine learning 

分 类 号：X172[环境科学与工程—环境科学]