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

DNA gyrase is a DNA topoisomerase indispensable for cellular functions in bacteria. We describe a novel, hitherto unknown, mechanism of specific inhibition of Mycobacterium smegmatis and Mycobacterium tuberculosis DNA gyrase by a monoclonal antibody (mAb). Binding of the mAb did not affect either Gy...

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Main Authors:	Manjunatha, Ujjini H., Maxwell, Anthony, Nagaraja, Valakunja
Format:	Online
Language:	English
Published:	Oxford University Press 2005
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1142348/

id	pubmed-1142348
recordtype	oai_dc
spelling	pubmed-11423482005-06-02 A monoclonal antibody that inhibits mycobacterial DNA gyrase by a novel mechanism Manjunatha, Ujjini H. Maxwell, Anthony Nagaraja, Valakunja Article DNA gyrase is a DNA topoisomerase indispensable for cellular functions in bacteria. We describe a novel, hitherto unknown, mechanism of specific inhibition of Mycobacterium smegmatis and Mycobacterium tuberculosis DNA gyrase by a monoclonal antibody (mAb). Binding of the mAb did not affect either GyrA–GyrB or gyrase–DNA interactions. More importantly, the ternary complex of gyrase–DNA–mAb retained the ATPase activity 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 heterotetrameric 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. Oxford University Press 2005 2005-06-01 /pmc/articles/PMC1142348/ /pubmed/15930158 http://dx.doi.org/10.1093/nar/gki622 Text en © The Author 2005. Published by Oxford University Press. All rights reserved
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Manjunatha, Ujjini H. Maxwell, Anthony Nagaraja, Valakunja
spellingShingle	Manjunatha, Ujjini H. Maxwell, Anthony Nagaraja, Valakunja A monoclonal antibody that inhibits mycobacterial DNA gyrase by a novel mechanism
author_facet	Manjunatha, Ujjini H. Maxwell, Anthony Nagaraja, Valakunja
author_sort	Manjunatha, Ujjini H.
title	A monoclonal antibody that inhibits mycobacterial DNA gyrase by a novel mechanism
title_short	A monoclonal antibody that inhibits mycobacterial DNA gyrase by a novel mechanism
title_full	A monoclonal antibody that inhibits mycobacterial DNA gyrase by a novel mechanism
title_fullStr	A monoclonal antibody that inhibits mycobacterial DNA gyrase by a novel mechanism
title_full_unstemmed	A monoclonal antibody that inhibits mycobacterial DNA gyrase by a novel mechanism
title_sort	monoclonal antibody that inhibits mycobacterial dna gyrase by a novel mechanism
description	DNA gyrase is a DNA topoisomerase indispensable for cellular functions in bacteria. We describe a novel, hitherto unknown, mechanism of specific inhibition of Mycobacterium smegmatis and Mycobacterium tuberculosis DNA gyrase by a monoclonal antibody (mAb). Binding of the mAb did not affect either GyrA–GyrB or gyrase–DNA interactions. More importantly, the ternary complex of gyrase–DNA–mAb retained the ATPase activity 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 heterotetrameric 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.
publisher	Oxford University Press
publishDate	2005
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1142348/
_version_	1611375235026649088

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

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