Identification and characterization of novel isothiazolones with potent bactericidal activity against multi-drug resistant Acinetobacter baumannii clinical isolates

• Published in: International journal of antimicrobial agents Vol. 53; no. 4; pp. 474 - 482
• Main Authors: Luna, Breanna L., Garcia, Javier A., Huang, Min, Ewing, Peter J., Valentine, Sonya C., Chu, Yi-Ming, Ye, Qi-Zhuang, Xu, H. Howard
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-04-2019
• Subjects: Acinetobacter baumannii; Antimicrobial susceptibility testing; Cytotoxicity; High-throughput screening; Isothiazolone; Time-kill assay; High-throughput screening; Antimicrobial susceptibility testing; Cytotoxicity; Acinetobacter baumannii; Time-kill assay; Isothiazolone; High throughput screening; Time kill assay
• ISSN: 0924-8579; 1872-7913
• DOI: 10.1016/j.ijantimicag.2018.12.007

•Acinetobacter baumannii is critical nosocomial pathogen resistant to multiple classes of antibiotics.•Through high-throughput screening, novel and potent isothiazolones were identified.•Several isothiazolones exhibit consistent and cidal activity against many clinical isolates of A. baumannii.•Presence of chloro-group on the heterocyclic ring or a fused benzene ring appears to be critical to activity.•These isothiazolones exhibit various degree of cytotoxicity to mammalian cells, with one compound possessing future development potential.
Acinetobacter baumannii has emerged as a globally important nosocomial pathogen characterized by an increased multi-drug resistance (MDR), leaving limited options for treating its infection. To identify novel antibacterial compounds with activity against clinical isolates of A. baumannii, we performed high-throughput screening against a chemical library of 42,944 compounds using nonpathogenic Escherichia coli MG1655 and identified 55 hit compounds. The antibacterial activities of 30 pure compounds were determined against MDR clinical isolates of A. baumannii obtained from Los Angeles County hospitals. Two isothiazolones identified, 5-chloro-2-(4-chloro-3-methylphenyl)-4-methyl-3(2H)-isothiazolone (Compound 6) and 5-chloro-2-(4-chlorophenyl)-4-methyl-3(2H)-isothiazolone (Compound 7), possess novel structure and exhibited consistent, potent and cidal activity against all 46 MDR A. baumannii clinical isolates and reference strains. Additionally, structure–activity relationship analysis involving several additional isothiazolones supports the link between a chloro-group on the heterocyclic ring or a fused benzene ring and the cidal activity. Attempts to obtain isothiazolone resistant mutants failed, consistent with the rapid cidal action and indicative of a complex mechanism of action. While cytotoxicity was observed with Compound 7, it had a therapeutic index value of 28 suggesting future therapeutic potential. Our results indicate that high-throughput screening of compound libraries followed by in vitro biological evaluations is a viable approach for the discovery of novel antibacterial agents to contribute in the fight against MDR bacterial pathogens.
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