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Biological evaluation of novel substituted chloroquinolines targeting mycobacterial ATP synthase

Authors
Journal
International Journal of Antimicrobial Agents
0924-8579
Publisher
Elsevier
Volume
41
Issue
1
Identifiers
DOI: 10.1016/j.ijantimicag.2012.09.012
Keywords
  • Atp Synthase
  • Mycobacterium Tuberculosis
  • Chloroquinolines
  • Non-Replicating Bacilli
  • Hypoxia
Disciplines
  • Biology

Abstract

Abstract The ATP synthase of Mycobacterium tuberculosis is a validated drug target against which a diarylquinoline drug is under clinical trials. The enzyme is crucial for the viability both of actively replicating and non-replicating/dormant M. tuberculosis. Enzyme levels drop drastically as the bacilli enter dormancy and hence an inhibitor would make the dormant bacilli even more vulnerable. In this study, a set of 18 novel substituted chloroquinolines were screened against Mycobacterium smegmatis ATP synthase; 6 compounds with the lowest 50% inhibitory concentration (IC50) values (0.36–1.83μM) were selected for further in vitro studies. All six compounds inhibited the growth of M. tuberculosis H37Rv in vitro, with minimum inhibitory concentrations (MICs) of 3.12μg/mL (two compounds) or 6.25μg/mL (four compounds). All of them were bactericidal to non-replicating M. tuberculosis H37Rv in hypoxic culture; three compounds caused a >2log10 reduction in CFU counts in 4 days at concentrations of 16× or 32× their MICs, compared with a 0.2log10 reduction by isoniazid and a >4log10 reduction by rifampicin at 100× their MICs. The compounds also contributed to a greater reduction in total cellular ATP of the bacilli compared with isoniazid and rifampicin during an exposure time of 18h. The compounds at 100μM caused only 5–35% inhibition of mouse liver mitochondrial ATP synthase, leading to selectivity indices ranging from >55-fold to >278-fold. In vitro cytotoxicity to the Vero cell line measured as the 50% cytotoxic concentration (CC50) of the compounds ranged between 55μg/mL and >300μg/mL.

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