New 2-Ethylthio-4-methylaminoquinazoline derivatives inhibiting two subunits of cytochrome bc1 in Mycobacterium tuberculosis

English version

Autoři: Andréanne Lupien ^aff001; Caroline Shi-Yan Foo ^aff001; Svetlana Savina ^aff002; Anthony Vocat ^aff001; Jérémie Piton ^aff001; Natalia Monakhova ^aff002; Andrej Benjak ^aff001; Dirk A. Lamprecht ^aff003; Adrie J. C. Steyn ^aff003; Kevin Pethe ^aff005; Vadim A. Makarov ^aff002; Stewart T. Cole ^aff001
Působiště autorů: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland ^aff001; Department of Stresses of Microorganisms, A. N. Bach Institute of Biochemistry, Moscow, Russian Federation ^aff002; Africa Health Research Institute, Durban, South Africa ^aff003; Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America ^aff004; Lee Kong Chian School of Medicine and School of Biological Sciences, Nanyang Technological University, Singapore ^aff005; Institut Pasteur, rue du Docteur Roux, France ^aff006
Vyšlo v časopise: New 2-Ethylthio-4-methylaminoquinazoline derivatives inhibiting two subunits of cytochrome bc1 in Mycobacterium tuberculosis. PLoS Pathog 16(1): e32767. doi:10.1371/journal.ppat.1008270
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008270

Souhrn

The emergence of multi-drug (MDR-TB) and extensively-drug resistant tuberculosis (XDR-TB) is a major threat to the global management of tuberculosis (TB) worldwide. New chemical entities are of need to treat drug-resistant TB. In this study, the mode of action of new, potent quinazoline derivatives was investigated against Mycobacterium tuberculosis (M. tb). Four derivatives 11626141, 11626142, 11626252 and 11726148 showed good activity (MIC ranging from 0.02–0.09 μg/mL) and low toxicity (TD₅₀ ≥ 5μg/mL) in vitro against M. tb strain H37Rv and HepG2 cells, respectively. 11626252 was the most selective compound from this series. Quinazoline derivatives were found to target cytochrome bc₁ by whole-genome sequencing of mutants selected with 11626142. Two resistant mutants harboured the transversion T943G (Trp312Gly) and the transition G523A (Gly175Ser) in the cytochrome bc₁ complex cytochrome b subunit (QcrB). Interestingly, a third mutant QuinR-M1 contained a mutation in the Rieske iron-sulphur protein (QcrA) leading to resistance to quinazoline and other QcrB inhibitors, the first report of cross-resistance involving QcrA. Modelling of both QcrA and QcrB revealed that all three resistance mutations are located in the stigmatellin pocket, as previously observed for other QcrB inhibitors such as Q203, AX-35, and lansoprazole sulfide (LPZs). Further analysis of the mode of action in vitro revealed that 11626252 exposure leads to ATP depletion, a decrease in the oxygen consumption rate and also overexpression of the cytochrome bd oxidase in M. tb. Our findings suggest that quinazoline-derived compounds are a new and attractive chemical entity for M. tb drug development targeting two separate subunits of the cytochrome bc₁ complex.

Klíčová slova:

Drug metabolism – Drug therapy – Extensively drug-resistant tuberculosis – Multi-drug-resistant tuberculosis – Mycobacterium tuberculosis – Respiratory infections – Transcriptome analysis – Tuberculosis

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