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Efficacy of beta-lactam/beta-lactamase inhibitor combination is linked to WhiB4-mediated changes in redox physiology of Mycobacterium tuberculosis

Mishra, Saurabh and Shukla, Prashant and Bhaskar, Ashima and Anand, Kushi and Baloni, Priyanka and Jha, Rajiv Kumar and Mohan, Abhilash and Rajmani, Raju S and Nagaraja, Valakunja and Chandra, Nagasuma and Singh, Amit (2017) Efficacy of beta-lactam/beta-lactamase inhibitor combination is linked to WhiB4-mediated changes in redox physiology of Mycobacterium tuberculosis. In: ELIFE, 6 .

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Official URL: http://dx.doi.org/10.7554/eLife.25624

Abstract

Mycobacterium tuberculosis (Mtb) expresses a broad-spectrum beta-lactamase (BlaC) that mediates resistance to one of the highly effective antibacterials, beta-lactams. Nonetheless, beta-lactams showed mycobactericidal activity in combination with beta-lactamase inhibitor, clavulanate (Clay). However, the mechanistic aspects of how Mtb responds to beta-lactams such as Amoxicillin in combination with Clay (referred as Augmentin AG]) are not clear. Here, we identified cytoplasmic redox potential and intracellular redox sensor, WhiB4, as key determinants of mycobacterial resistance against AG. Using computer-based, biochemical, redox-biosensor, and genetic strategies, we uncovered a functional linkage between specific determinants of beta-lactam resistance (e.g. beta-lactamase) and redox potential in Mtb. We also describe the role of WhiB4 in coordinating the activity of beta-lactamase in a redox-dependent manner to tolerate AG. Disruption of WhiB4 enhances AG tolerance, whereas overexpression potentiates AG activity against drug-resistant Mtb. Our findings suggest that AG can be exploited to diminish drug-resistance in Mtb through redox-based interventions.

Item Type: Journal Article
Additional Information: Copyright for this article belongs to the ELIFE SCIENCES PUBLICATIONS LTD, SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND
Department/Centre: Division of Biological Sciences > Biochemistry
Division of Biological Sciences > Molecular Biophysics Unit
Division of Biological Sciences > Microbiology & Cell Biology
Depositing User: Id for Latest eprints
Date Deposited: 08 Jul 2017 07:17
Last Modified: 08 Jul 2017 07:17
URI: http://eprints.iisc.ac.in/id/eprint/57328

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