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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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 |
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Publication: | ELIFE |
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 |
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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