Please use this identifier to cite or link to this item: http://lib.jncasr.ac.in:8080/jspui/handle/10572/2600
Title: Molecular Basis for the Differential Quinolone Susceptibility of Mycobacterial DNA Gyrase
Authors: Kumar, Rupesh
Madhumathi, Bhavani Shankar
Nagaraja, V.
Keywords: Microbiology
Pharmacology & Pharmacy
Resistance-Determining Region
Escherichia-Coli
Topoisomerase-Iv
Fluoroquinolone Action
Iia Topoisomerases
Magnesium-Ions
Mechanism
Binding
Inhibition
Tuberculosis
Issue Date: 2014
Publisher: American Society Microbiology
Citation: Kumar, R; Madhumathi, BS; Nagaraja, V, Molecular Basis for the Differential Quinolone Susceptibility of Mycobacterial DNA Gyrase. Antimicrobial Agents And Chemotherapy 2014, 58 (4) 2013-2020, http://dx.doi.org/10.1128/AAC.01958-13
Antimicrobial Agents And Chemotherapy
58
4
Abstract: DNA gyrase is a type II topoisomerase that catalyzes the introduction of negative supercoils in the genomes of eubacteria. Fluoroquinolones (FQs), successful as drugs clinically, target the enzyme to trap the gyrase-DNA complex, leading to the accumulation of double-strand breaks in the genome. Mycobacteria are less susceptible to commonly used FQs. However, an 8-methoxy-substituted FQ, moxifloxacin (MFX), is a potent antimycobacterial, and a higher susceptibility of mycobacterial gyrase to MFX has been demonstrated. Although several models explain the mechanism of FQ action and gyrase-DNA-FQ interaction, the basis for the differential susceptibility of mycobacterial gyrase to various FQs is not understood. We have addressed the basis of the differential susceptibility of the gyrase and revisited the mode of action of FQs. We demonstrate that FQs bind both Escherichia coli and Mycobacterium tuberculosis gyrases in the absence of DNA and that the addition of DNA enhances the drug binding. The FQs bind primarily to the GyrA subunit of mycobacterial gyrase, while in E. coli holoenzyme is the target. The binding of MFX to GyrA of M. tuberculosis correlates with its effectiveness as a better inhibitor of the enzyme and its efficacy in cell killing.
Description: Restricted Access
URI: http://hdl.handle.net/10572/2600
ISSN: 0066-4804
Appears in Collections:Research Articles (Nagaraja, V.)

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