Version 1
: Received: 30 March 2022 / Approved: 1 April 2022 / Online: 1 April 2022 (07:22:46 CEST)
Version 2
: Received: 23 May 2022 / Approved: 24 May 2022 / Online: 24 May 2022 (11:32:52 CEST)
How to cite:
S, S.; Muralikrishnan, B.; Bhat, S.; Ajay Kumar, R.; Kurthkoti, K. Overexpression of a Membrane Transport System MSMEG_1381 and MSMEG_1382 Confers Multidrug Resistance in Mycobacterium smegmatis. Preprints2022, 2022040003. https://doi.org/10.20944/preprints202204.0003.v1.
S, S.; Muralikrishnan, B.; Bhat, S.; Ajay Kumar, R.; Kurthkoti, K. Overexpression of a Membrane Transport System MSMEG_1381 and MSMEG_1382 Confers Multidrug Resistance in Mycobacterium smegmatis. Preprints 2022, 2022040003. https://doi.org/10.20944/preprints202204.0003.v1.
Cite as:
S, S.; Muralikrishnan, B.; Bhat, S.; Ajay Kumar, R.; Kurthkoti, K. Overexpression of a Membrane Transport System MSMEG_1381 and MSMEG_1382 Confers Multidrug Resistance in Mycobacterium smegmatis. Preprints2022, 2022040003. https://doi.org/10.20944/preprints202204.0003.v1.
S, S.; Muralikrishnan, B.; Bhat, S.; Ajay Kumar, R.; Kurthkoti, K. Overexpression of a Membrane Transport System MSMEG_1381 and MSMEG_1382 Confers Multidrug Resistance in Mycobacterium smegmatis. Preprints 2022, 2022040003. https://doi.org/10.20944/preprints202204.0003.v1.
Abstract
Mycobacterium tuberculosis is a leading cause of human mortality worldwide and the emergence of drug-resistantstrains, demands the discovery of new classes of antimycobacterials that can be employed in the therapeutic pipeline. Previously, a secondary metabolite Chrysomycin A, isolated from Streptomyces sp. OA161 was shown to have potent bactericidal activity against drug-resistant clinical isolates of M. tuberculosis and different species of mycobacteria. The antibiotic inhibits the mycobacterial topoisomerase I and DNA gyrase leading to bacterial death, but the mechanisms that could cause resistance are currently unknown. To further understand the resistance mechanism, spontaneous resistance mutants were isolated and subjected to whole-genome sequencing. Mutation in a TetR family transcriptional regulator MSMEG_1380 was identified in the resistant isolates and was close to an operon encoding membrane protein MSMEG_1381 and MSMEG_1382. Sequence analysis and modeling studies indicated that they are components of the Mmp family of efflux pumps and over-expression of either the operon or individual genes conferred resistance to chrysomycin A, isoniazid, and ethambutol that are in TB therapy. Our study highlights the role of membrane transporter proteins in conferring multiple drug resistance and the utility of recombinant strains overexpressing membrane transporters in the drug screening pipeline.
Keywords
Drug resistance; Efflux pump; TetR transcriptional regulator; Mycobacteria; MmpL
Subject
LIFE SCIENCES, Microbiology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
