Identifying and Tackling Emergent Vulnerability in Drug-Resistant Mycobacteria

Padiadpu, Jyothi and Baloni, Priyanka and Anand, Kushi and Munshi, MohamedHusen and Thakur, Chandrani and Mohan, Abhilash and Singh, Amit and Chandra, Nagasuma (2016) Identifying and Tackling Emergent Vulnerability in Drug-Resistant Mycobacteria. In: ACS INFECTIOUS DISEASES, 2 (9). pp. 592-607.

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Abstract

The global mechanisms and associated molecular alterations that occur in drug-resistant mycobacteria are poorly understood. To address this, we obtain genomics data and then construct a genomescale response network in isoniazid-resistant Mycobacterium smegmatis and apply a network-mining algorithm. Through this, we decipher global alterations in an unbiased manner and identify emergent vulnerabilities in resistant bacilli, of which redox response was prominent. Using phenotypic profiling, we find that resistant bacilli exhibit collateral sensitivity to several compounds that block antioxidant responses. We find that nanogram/milliliter concentrations of ebselen, vancomycin, and phenylarsine oxide, in combination with isoniazid, are highly effective against Mycobacterium tuberculosis H37Rv and three clinical drug-resistant strains. Dynamic measurements of cytoplasmic redox potential revealed a surprisingly diminished capacity of clinical drug-resistant strains to counteract oxidative stress, providing a mechanistic basis for efficient and synergistic mycobactericidal activity of the drug combinations. Ebselen and vancomycin appear to be promising repurposable drugs.

Item Type:	Journal Article
Publication:	ACS INFECTIOUS DISEASES
Additional Information:	Copy right for this article belongs to the AMER CHEMICAL SOC, 1155 16TH ST, NW, WASHINGTON, DC 20036 USA
Department/Centre:	Division of Biological Sciences > Biochemistry Division of Biological Sciences > Molecular Biophysics Unit Division of Biological Sciences > Microbiology & Cell Biology Division of Biological Sciences > Centre for Infectious Disease Research Division of Interdisciplinary Sciences > Supercomputer Education & Research Centre
Date Deposited:	22 Oct 2016 10:12
Last Modified:	22 Oct 2016 10:12
URI:	http://eprints.iisc.ac.in/id/eprint/55082

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