期刊
ELIFE
卷 6, 期 -, 页码 -出版社
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.25624
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资金
- Department of Biotechnology, Ministry of Science and Technology [BT/PR5020/MED/29/1454/2012]
- Wellcome [WT-DBT/500034-Z-09-Z]
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.
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