A monoclonal antibody that inhibits mycobacterial DNA gyrase by a novel mechanism

Manjunatha, Ujjini H and Maxwell, Anthony and Nagaraja, Valakunja (2005) A monoclonal antibody that inhibits mycobacterial DNA gyrase by a novel mechanism. In: Nucleic Acids Research, 33 (10). pp. 3085-3094.

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Abstract

DNA gyrase is a DNA topoisomerase indispensable for cellular functions in bacteria. We describe a novel, hither to unknown, mechanism ofspecific inhibition of Mycobacterium smegmatis and Mycobacterium tuberculosis DNA gyrase by a monoclonal antibody (mAb). Binding of them Ab did not affect either GyrA-GyrB or gyrase-DNA interactions. More importantly, the ternary complex of gyrase-DNA-mAb retained the ATP aseactivity of the enzyme and was competent to catalyse DNA cleavage-religation reactions, implying a new mode of action different from other classes of gyrase inhibitors. DNA gyrase purified from fluoroquinolone-resistant strains of M.tuberculosis and M.smegmatis were inhibited by the mAb. The absence of cross-resistance of the drug-resistant enzymes from two different sources to the antibody-mediated inhibition corroborates the new mechanism of inhibition. We suggest that binding of the mAb in the proximity of the primary dimer interface region of GyrA in the hetero tetrameric enzyme appears to block the release of the transported segment after strand passage, leading to enzyme inhibition. The specific inhibition of mycobacterial DNA gyrase with the mAb opens up new avenues for designing novel lead molecules for drug discovery and for probing gyrase mechanism.

Item Type:	Journal Article
Publication:	Nucleic Acids Research
Publisher:	Oxford University Press
Additional Information:	Copyright for this article belongs to Oxford University Press.
Department/Centre:	Division of Biological Sciences > Microbiology & Cell Biology
Date Deposited:	24 Aug 2005
Last Modified:	19 Sep 2010 04:19
URI:	http://eprints.iisc.ac.in/id/eprint/3554

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