Identification of isothiazolones analogues as potent bactericidal agents against antibiotic resistant CRE and MRSA strains
Wenbin Jin,
Chen Xu,
Ning Dong,
Kaichao Chen,
Die Zhang,
Jinhua Ning,
Yunbing Li,
Guangfen Zhang,
Jin Ke,
Anguo Hou,
Linyun Chen,
Sheng Chen,
Kin-Fai Chan
Affiliations
Wenbin Jin
Key Laboratory of External Drug Delivery System and Preparation Technology in Universities of Yunnan and Faculty of Chinese Materia Medica, Yunnan University of Chinese Medicine
Chen Xu
State Key Laboratory of Chemical Biology and Drug Discovery and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University
Ning Dong
State Key Laboratory of Chemical Biology and Drug Discovery and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University
Kaichao Chen
State Key Laboratory of Chemical Biology and Drug Discovery and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University
Die Zhang
Key Laboratory of External Drug Delivery System and Preparation Technology in Universities of Yunnan and Faculty of Chinese Materia Medica, Yunnan University of Chinese Medicine
Jinhua Ning
Key Laboratory of External Drug Delivery System and Preparation Technology in Universities of Yunnan and Faculty of Chinese Materia Medica, Yunnan University of Chinese Medicine
Yunbing Li
Department of Medical Microbiology, School of Biology and Basic Medical Sciences, Suzhou Medical College of Soochow University
Guangfen Zhang
Department of Medical Microbiology, School of Biology and Basic Medical Sciences, Suzhou Medical College of Soochow University
Jin Ke
Key Laboratory of External Drug Delivery System and Preparation Technology in Universities of Yunnan and Faculty of Chinese Materia Medica, Yunnan University of Chinese Medicine
Anguo Hou
Key Laboratory of External Drug Delivery System and Preparation Technology in Universities of Yunnan and Faculty of Chinese Materia Medica, Yunnan University of Chinese Medicine
Linyun Chen
Key Laboratory of External Drug Delivery System and Preparation Technology in Universities of Yunnan and Faculty of Chinese Materia Medica, Yunnan University of Chinese Medicine
Sheng Chen
Department of Food Science and Nutrition, The Hong Kong Polytechnic University
Kin-Fai Chan
State Key Laboratory of Chemical Biology and Drug Discovery and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University
Abstract Carbapenem-resistant Enterobacterales (CRE) has emerged as a worldwide spread nosocomial superbug exhibiting antimicrobial resistance (AMR) to all current antibiotics, leaving limited options for treating its infection. To discovery novel antibiotics against CRE, we designed and synthesized a series of 14 isothiazol-3(2H)-one analogues subjected to antibacterial activity evaluation against Escherichia coli (E. coli) BL21 (NDM-1) and clinical strain E. coli HN88 for investigating their structure–activity relationships (SAR). The results suggested that 5-chloroisothiazolone core with an N-(4-chlorophenyl) substitution 5a was the most potent antibacterial activity against the E. coli BL21 (NDM-1) with MIC value of less than 0.032 μg/mL, which was at least 8000-fold higher than the positive control Meropenem (MRM). It also displayed 2048-fold potent than the positive control MRM against E. coli HN88. Additionally, SAR analysis supported the conclusion that compounds with a chloro-group substituted on the 5-position of the heterocyclic ring was much more potent than other positions. The board spectrum analysis suggested that compound 5a showed a promising antimicrobial activity on MRSA and CRE pathogens. Meanwhile, cytotoxicity study of compound 5a suggested that it had a therapeutic index value of 875, suggesting future therapeutic potential. In vivo efficacy study declared that compound 5a could also protect the BALB/c mice against American type culture collection (ATCC) 43,300. Further screening of our compounds against a collection of CRE strains isolated from patients indicated that compound 5 g displayed much stronger antibacterial activity compared with MRM. In conclusion, our studies indicated that isothiazolones analogues could be potent bactericidal agents against CRE and MRSA pathogens.
