Genetic and chemical validation identifies Mycobacterium tuberculosis topoisomerase I as an attractive anti-tubercular target.

Autor: Ravishankar S; AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India. Electronic address: mailsuravi01@gmail.com., Ambady A; AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Awasthy D; AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Mudugal NV; AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Menasinakai S; AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Jatheendranath S; AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Guptha S; AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Sharma S; AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Balakrishnan G; AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Nandishaiah R; AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Ramachandran V; AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Eyermann CJ; AstraZeneca Infection, Innovative Medicines, 35 Gatehouse Drive, Waltham, MA 02451, United States., Reck F; AstraZeneca Infection, Innovative Medicines, 35 Gatehouse Drive, Waltham, MA 02451, United States., Rudrapatna S; AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Sambandamurthy VK; AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Sharma UK; AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India.
Jazyk: angličtina
Zdroj: Tuberculosis (Edinburgh, Scotland) [Tuberculosis (Edinb)] 2015 Sep; Vol. 95 (5), pp. 589-98. Date of Electronic Publication: 2015 May 27.
DOI: 10.1016/j.tube.2015.05.004
Abstrakt: DNA topoisomerases perform the essential function of maintaining DNA topology in prokaryotes. DNA gyrase, an essential enzyme that introduces negative supercoils, is a clinically validated target. However, topoisomerase I (Topo I), an enzyme responsible for DNA relaxation has received less attention as an antibacterial target, probably due to the ambiguity over its essentiality in many organisms. The Mycobacterium tuberculosis genome harbors a single topA gene with no obvious redundancy in its function suggesting an essential role. The topA gene could be inactivated only in the presence of a complementing copy of the gene in M. tuberculosis. Furthermore, down-regulation of topA in a genetically engineered strain of M. tuberculosis resulted in loss of bacterial viability which correlated with a concomitant depletion of intracellular Topo I levels. The topA knockdown strain of M. tuberculosis failed to establish infection in a murine model of TB and was cleared from lungs in two months post infection. Phenotypic screening of a Topo I overexpression strain led to the identification of an inhibitor, thereby providing chemical validation of this target. Thus, our work confirms the attractiveness of Topo I as an anti-mycobacterial target.
(Copyright © 2015 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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