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Article: Molecular characterization of fluoroquinolone resistance in Mycobacterium tuberculosis: Functional analysis of gyrA mutation at position 74

TitleMolecular characterization of fluoroquinolone resistance in Mycobacterium tuberculosis: Functional analysis of gyrA mutation at position 74
Authors
Issue Date2011
Citation
Antimicrobial Agents And Chemotherapy, 2011, v. 55 n. 2, p. 608-614 How to Cite?
AbstractA PCR-sequencing assay was evaluated for direct detection of mutations in the quinolone resistance-determining region (QRDR) of gyrase A (gyrA) gene in fluoroquinolone-resistant Mycobacterium tuberculosis in respiratory specimens. As determined by gyrA QRDR analysis, complete concordance of genotypic and phenotypic fluoroquinolone resistance was demonstrated. Our results indicate that the assay is a rapid and reliable method for the diagnosis of fluoroquinolone-resistant tuberculosis, facilitating timely clinical management and public health control. Using the assay, we detected a novel gyrA Ala74Ser mutation in M. tuberculosis directly from sputum specimens. The functional effect of the Ala74Ser mutant was verified through the study of the DNA supercoiling inhibitory activity of fluoroquinolones against the recombinant gyrase. The drug-mediated gyrase-DNA cleavage complex model suggests perturbation of the gyrA-gyrA dimer interface caused by the Ala74Ser mutation probably disturbs the putative quinolone binding pocket and leads to the reduction of the drug binding affinity. A number of gyrA mutations (Glu21Gln, Ser95Thr, and Gly668Asp) were also characterized to be natural polymorphisms not associated with fluoroquinolone resistance. Copyright © 2011, American Society for Microbiology. All Rights Reserved.
Persistent Identifierhttp://hdl.handle.net/10722/157614
ISSN
2015 Impact Factor: 4.415
2015 SCImago Journal Rankings: 2.322
ISI Accession Number ID
Funding AgencyGrant Number
National Chinese Grant for Infectious Diseases2008ZX10003-012
Food and Health Bureau of the Hong Kong SAR Government
Funding Information:

This study was supported by grants from the National Chinese Grant for Infectious Diseases (grant 2008ZX10003-012) and the Research Fund for the Control of Infectious Diseases of the Food and Health Bureau of the Hong Kong SAR Government.

References

 

DC FieldValueLanguage
dc.contributor.authorLau, RWTen_US
dc.contributor.authorHo, PLen_US
dc.contributor.authorKao, RYTen_US
dc.contributor.authorYew, WWen_US
dc.contributor.authorLau, TCKen_US
dc.contributor.authorCheng, VCCen_US
dc.contributor.authorYuen, KYen_US
dc.contributor.authorTsui, SKWen_US
dc.contributor.authorChen, Xen_US
dc.contributor.authorYam, WCen_US
dc.date.accessioned2012-08-08T08:51:41Z-
dc.date.available2012-08-08T08:51:41Z-
dc.date.issued2011en_US
dc.identifier.citationAntimicrobial Agents And Chemotherapy, 2011, v. 55 n. 2, p. 608-614en_US
dc.identifier.issn0066-4804en_US
dc.identifier.urihttp://hdl.handle.net/10722/157614-
dc.description.abstractA PCR-sequencing assay was evaluated for direct detection of mutations in the quinolone resistance-determining region (QRDR) of gyrase A (gyrA) gene in fluoroquinolone-resistant Mycobacterium tuberculosis in respiratory specimens. As determined by gyrA QRDR analysis, complete concordance of genotypic and phenotypic fluoroquinolone resistance was demonstrated. Our results indicate that the assay is a rapid and reliable method for the diagnosis of fluoroquinolone-resistant tuberculosis, facilitating timely clinical management and public health control. Using the assay, we detected a novel gyrA Ala74Ser mutation in M. tuberculosis directly from sputum specimens. The functional effect of the Ala74Ser mutant was verified through the study of the DNA supercoiling inhibitory activity of fluoroquinolones against the recombinant gyrase. The drug-mediated gyrase-DNA cleavage complex model suggests perturbation of the gyrA-gyrA dimer interface caused by the Ala74Ser mutation probably disturbs the putative quinolone binding pocket and leads to the reduction of the drug binding affinity. A number of gyrA mutations (Glu21Gln, Ser95Thr, and Gly668Asp) were also characterized to be natural polymorphisms not associated with fluoroquinolone resistance. Copyright © 2011, American Society for Microbiology. All Rights Reserved.en_US
dc.languageengen_US
dc.relation.ispartofAntimicrobial Agents and Chemotherapyen_US
dc.subject.meshAnti-Infective Agents - Pharmacologyen_US
dc.subject.meshDna Gyrase - Chemistry - Geneticsen_US
dc.subject.meshDrug Resistance, Bacterial - Geneticsen_US
dc.subject.meshFluoroquinolones - Pharmacologyen_US
dc.subject.meshHumansen_US
dc.subject.meshMicrobial Sensitivity Testsen_US
dc.subject.meshMutationen_US
dc.subject.meshMycobacterium Tuberculosis - Drug Effects - Geneticsen_US
dc.subject.meshPolymerase Chain Reaction - Methodsen_US
dc.subject.meshSequence Analysis, Dnaen_US
dc.subject.meshTuberculosis - Diagnosis - Microbiologyen_US
dc.titleMolecular characterization of fluoroquinolone resistance in Mycobacterium tuberculosis: Functional analysis of gyrA mutation at position 74en_US
dc.typeArticleen_US
dc.identifier.emailHo, PL:plho@hkucc.hku.hken_US
dc.identifier.emailKao, RYT:rytkao@hkucc.hku.hken_US
dc.identifier.emailYuen, KY:kyyuen@hkucc.hku.hken_US
dc.identifier.emailYam, WC:wcyam@hkucc.hku.hken_US
dc.identifier.authorityHo, PL=rp00406en_US
dc.identifier.authorityKao, RYT=rp00481en_US
dc.identifier.authorityYuen, KY=rp00366en_US
dc.identifier.authorityYam, WC=rp00313en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1128/AAC.00920-10en_US
dc.identifier.pmid20956608en_US
dc.identifier.scopuseid_2-s2.0-78751697747en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-78751697747&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume55en_US
dc.identifier.issue2en_US
dc.identifier.spage608en_US
dc.identifier.epage614en_US
dc.identifier.isiWOS:000286422500021-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridLau, RWT=36664762000en_US
dc.identifier.scopusauthoridHo, PL=7402211363en_US
dc.identifier.scopusauthoridKao, RYT=7101675499en_US
dc.identifier.scopusauthoridYew, WW=7005934631en_US
dc.identifier.scopusauthoridLau, TCK=36981810500en_US
dc.identifier.scopusauthoridCheng, VCC=23670479400en_US
dc.identifier.scopusauthoridYuen, KY=36078079100en_US
dc.identifier.scopusauthoridTsui, SKW=7004961364en_US
dc.identifier.scopusauthoridChen, X=8710357400en_US
dc.identifier.scopusauthoridYam, WC=7004281720en_US

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