期刊
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
卷 65, 期 8, 页码 -出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.00011-21
关键词
Mycobacterium tuberculosis; drug resistance; bactericidal activity; isatin-isoniazid hybrids; KatG; InhA; mycolic acids
资金
- Investissements d'Avenir program [ANR-10-LABX-12-01]
- Association Gregory Lemarchal and Vaincre la Mucoviscidose [RIF20180502320]
- Department of Science and Technology, New Delhi, India, under the INSPIRE program [IF160180]
- Council of Scientific and Industrial Research (CSIR), New Delhi, India [02(0293)/17/EMR-II]
- National Health and Medical Research Council (NHMRC) of Australia [1175134]
- University of Technology Sydney - NHMRC project grant [1141142]
- NHMRC Centre of Research Excellence in TB Control [1153493]
- National Health and Medical Research Council of Australia [1153493] Funding Source: NHMRC
The designed and synthesized isatin-isoniazid hybrids exhibit high antimycobacterial activity against tuberculosis, well-tolerated with good selectivity in kidney cells, and are effective in infected macrophages, indicating their potential as promising antitubercular compounds for further evaluation in preclinical settings.
Tuberculosis remains a leading cause of mortality among infectious diseases worldwide, prompting the need to discover new drugs to fight this disease. We report here the design, synthesis, and antimycobacterial activity of isatin-mono/bis-isoniazid hybrids. Most of the compounds exhibited very high activity against Mycobacterium tuberculosis, with MICs in the range of 0.195 to 0.39 mu g/ml, and exerted a more potent bactericidal effect than the standard antitubercular drug isoniazid (INH). Importantly, these compounds were found to be well tolerated at high doses (>200 mu g/ml) on Vero kidney cells, leading to high selectivity indices. Two of the most promising hybrids were evaluated for activity in THP-1 macrophages infected with M. tuberculosis, among which compound 11e was found to be slightly more effective than INH. Overexpression of InhA along with cross-resistance determination of the most potent compounds, selection of resistant mutants, and biochemical analysis, allowed us to decipher their mode of action. These compounds effectively inhibited mycolic acid biosynthesis and required KatG to exert their biological effects. Collectively, this suggests that the synthesized isatin-INH hybrids are promising antitubercular molecules for further evaluation in preclinical settings.
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