Efficacy of β-lactam/β-lactamase inhibitor combination is linked to WhiB4-mediated changes in redox physiology of Mycobacterium tuberculosis
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 mechan...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2017-05-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/25624 |
| _version_ | 1811180696719327232 |
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| author | Saurabh Mishra Prashant Shukla Ashima Bhaskar Kushi Anand Priyanka Baloni Rajiv Kumar Jha Abhilash Mohan Raju S Rajmani Valakunja Nagaraja Nagasuma Chandra Amit Singh |
| author_facet | Saurabh Mishra Prashant Shukla Ashima Bhaskar Kushi Anand Priyanka Baloni Rajiv Kumar Jha Abhilash Mohan Raju S Rajmani Valakunja Nagaraja Nagasuma Chandra Amit Singh |
| author_sort | Saurabh Mishra |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T09:07:39Z |
| format | Article |
| id | doaj.art-d811501a595641efbdfc414e2992d5c8 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:07:39Z |
| publishDate | 2017-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-d811501a595641efbdfc414e2992d5c82022-12-22T04:32:36ZengeLife Sciences Publications LtdeLife2050-084X2017-05-01610.7554/eLife.25624Efficacy of β-lactam/β-lactamase inhibitor combination is linked to WhiB4-mediated changes in redox physiology of Mycobacterium tuberculosisSaurabh Mishra0https://orcid.org/0000-0003-1590-884XPrashant Shukla1Ashima Bhaskar2Kushi Anand3Priyanka Baloni4Rajiv Kumar Jha5Abhilash Mohan6Raju S Rajmani7Valakunja Nagaraja8Nagasuma Chandra9Amit Singh10https://orcid.org/0000-0001-6761-1664Microbiology and Cell Biology, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, IndiaMicrobiology and Cell Biology, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India; International Centre for Genetic Engineering and Biotechnology, New Delhi, IndiaNational Institute of Immunology, New Delhi, IndiaMicrobiology and Cell Biology, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, IndiaDepartment of Biochemistry, Indian Institute of Science, Bangalore, India; Molecular Biophysics Unit, Indian Institute of Science, Bangalore, IndiaMicrobiology and Cell Biology, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, IndiaDepartment of Biochemistry, Indian Institute of Science, Bangalore, IndiaMicrobiology and Cell Biology, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, IndiaMicrobiology and Cell Biology, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India; Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, IndiaDepartment of Biochemistry, Indian Institute of Science, Bangalore, IndiaMicrobiology and Cell Biology, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, IndiaMycobacterium 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.https://elifesciences.org/articles/25624Mycobacterium tuberculosisMycothioldrug toleranceAmoxicillin-ClavulanatePeptidoglycanpersistence |
| spellingShingle | Saurabh Mishra Prashant Shukla Ashima Bhaskar Kushi Anand Priyanka Baloni Rajiv Kumar Jha Abhilash Mohan Raju S Rajmani Valakunja Nagaraja Nagasuma Chandra Amit Singh Efficacy of β-lactam/β-lactamase inhibitor combination is linked to WhiB4-mediated changes in redox physiology of Mycobacterium tuberculosis eLife Mycobacterium tuberculosis Mycothiol drug tolerance Amoxicillin-Clavulanate Peptidoglycan persistence |
| title | Efficacy of β-lactam/β-lactamase inhibitor combination is linked to WhiB4-mediated changes in redox physiology of Mycobacterium tuberculosis |
| title_full | Efficacy of β-lactam/β-lactamase inhibitor combination is linked to WhiB4-mediated changes in redox physiology of Mycobacterium tuberculosis |
| title_fullStr | Efficacy of β-lactam/β-lactamase inhibitor combination is linked to WhiB4-mediated changes in redox physiology of Mycobacterium tuberculosis |
| title_full_unstemmed | Efficacy of β-lactam/β-lactamase inhibitor combination is linked to WhiB4-mediated changes in redox physiology of Mycobacterium tuberculosis |
| title_short | Efficacy of β-lactam/β-lactamase inhibitor combination is linked to WhiB4-mediated changes in redox physiology of Mycobacterium tuberculosis |
| title_sort | efficacy of β lactam β lactamase inhibitor combination is linked to whib4 mediated changes in redox physiology of mycobacterium tuberculosis |
| topic | Mycobacterium tuberculosis Mycothiol drug tolerance Amoxicillin-Clavulanate Peptidoglycan persistence |
| url | https://elifesciences.org/articles/25624 |
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