title: Synthesis and evaluation of isatin-β-thiosemicarbazones as novel agents against antibiotic-resistant Gram-positive bacterial species.
abstract: Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) have caused an increasing mortality rate, which means that antibiotic resistance is becoming an important health issue. In the course to screen new agents for resistant bacteria, we identified that a series of isatin-β-thiosemicarbazones (IBTs) could inhibit the growth of MRSA and VRE. This was the first time that the "familiar" IBT compounds exhibited significant anti Gram-positive pathogen activity. Against a clinical isolated MRSA strain, 20 of the 51 synthesized compounds showed minimum inhibitory concentration (MIC) data of 0.78 mg/L and another 12 novel compounds had MICs of 0.39 mg/L. Moreover, these compounds also inhibited Enterococcus faecalis and VRE at similar levels, indicating that IBTs might have different mode of action compared with vancomycin. For these IBTs, comparative field analysis (CoMFA) models were further established to understand the structure-activity relationships in order to design new compounds from steric and electrostatic contributions. This work has suggested that IBTs can be considered as potential lead compounds to discover antibacterial inhibitors to combat drug resistance.
authors.affiliation: State-Key Laboratory and Research Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China.
authors.forename: Xu-Meng
authors.initials: XM
authors.lastname: Zhang
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Guo
authors.affiliation: State-Key Laboratory and Research Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China.
authors.forename: Zai-Shun
authors.initials: ZS
authors.lastname: Li
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Fu-Hang
authors.initials: FH
authors.lastname: Song
authors.affiliation: State-Key Laboratory and Research Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China.
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Wang
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: daihq@im.ac.cn.
authors.forename: Huan-Qin
authors.initials: HQ
authors.lastname: Dai
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: zhanglixin@im.ac.cn.
authors.forename: Li-Xin
authors.initials: LX
authors.lastname: Zhang
authors.affiliation: State-Key Laboratory and Research Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China. Electronic address: nkwjg@nankai.edu.cn.
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Wang
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007510:Isatin / Q000737:chemistry / Q000494:pharmacology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000737:chemistry / Q000494:pharmacology*; D065507:Vancomycin-Resistant Enterococci / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D013882:Thiosemicarbazones; D007510:Isatin
keywords: In vitro activity; Isatin-β-thiosemicarbazone; Methicillin-resistant Staphylococcus aureus; Structure–activity relationships; Vancomycin-resistant Enterococcus