| Autor: |
Mishra S; Microbiology and Cell Biology, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India., Shukla P; Microbiology and Cell Biology, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India.; International Centre for Genetic Engineering and Biotechnology, New Delhi, India., Bhaskar A; National Institute of Immunology, New Delhi, India., Anand K; Microbiology and Cell Biology, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India., Baloni P; Department of Biochemistry, Indian Institute of Science, Bangalore, India.; Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India., Jha RK; Microbiology and Cell Biology, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India., Mohan A; Department of Biochemistry, Indian Institute of Science, Bangalore, India., Rajmani RS; Microbiology and Cell Biology, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India., Nagaraja V; Microbiology and Cell Biology, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India.; Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India., Chandra N; Department of Biochemistry, Indian Institute of Science, Bangalore, India., Singh A; Microbiology and Cell Biology, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India. |
| Abstrakt: |
Mycobacterium tuberculosis ( Mtb ) expresses a broad-spectrum β-lactamase (BlaC) that mediates resistance to one of the highly effective antibacterials, β-lactams. Nonetheless, β-lactams showed mycobactericidal activity in combination with β-lactamase inhibitor, clavulanate (Clav). However, the mechanistic aspects of how Mtb responds to β-lactams such as Amoxicillin in combination with Clav (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 β-lactam resistance (e.g. β-lactamase) and redox potential in Mtb . We also describe the role of WhiB4 in coordinating the activity of β-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. |
