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Article: Mutations outside the rifampicin resistance-determining region associated with rifampicin resistance in Mycobacterium tuberculosis

TitleMutations outside the rifampicin resistance-determining region associated with rifampicin resistance in Mycobacterium tuberculosis
Authors
Issue Date2011
PublisherOxford University Press. The Journal's web site is located at http://jac.oxfordjournals.org/
Citation
Journal of Antimicrobial Chemotherapy, 2011, v. 66 n. 4, p. 730-733 How to Cite?
AbstractObjectives: Ninety-six percent of rifampicin resistance in Mycobacterium tuberculosis was shown to be associated with mutations inside the 81 bp rifampicin resistance-determining region (RRDR) located in the centre of the rpoB gene. The detection of rifampicin resistance by targeting the RRDR failed to match with a resistant phenotype in 4% of all cases. Our study aims to identify the mutations outside the RRDR that are associated with rifampicin resistance in M. tuberculosis. Methods and results: Among 50 rifampicin-resistant and 20 rifampicin-susceptible clinical isolates of M. tuberculosis, 2 of the rifampicin-resistant isolates did not harbour any known mutations in the RRDR. Sequencing analysis of the whole rpoB gene identified two rare mutations, V146F and I572F. A molecular structure model based on Thermus thermophilus RpoB revealed that both these substituted amino acids are located in close proximity to the rifampicin-binding pocket of the β-subunit. Substitutions of simple amino acids for bulky ones are likely to affect the protein-drug interaction. Cloning and transformation of the mutated rpoB gene into wild-type Mycobacterium smegmatis and M. tuberculosis successfully elevated the MIC of rifampicin and conferred the rifampicin resistance phenotype. Conclusions: Our study showed that amino acid positions 146 and 572 are associated with rifampicin resistance in M. tuberculosis in addition to the RRDR. Molecular assays for identifying rifampicin-resistant M. tuberculosis might be improved in terms of accuracy by including these two positions. © The Author 2011. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/157625
ISSN
2015 Impact Factor: 4.919
2015 SCImago Journal Rankings: 2.157
ISI Accession Number ID
Funding AgencyGrant Number
National Chinese Grant for Infectious Diseases2008ZX10003-012
Funding Information:

This work was supported by a grant from the National Chinese Grant for Infectious Diseases (grant number 2008ZX10003-012).

References

 

DC FieldValueLanguage
dc.contributor.authorSiu, GKHen_US
dc.contributor.authorZhang, Yen_US
dc.contributor.authorLau, TCKen_US
dc.contributor.authorLau, RWTen_US
dc.contributor.authorHo, PLen_US
dc.contributor.authorYew, WWen_US
dc.contributor.authorTsui, SKWen_US
dc.contributor.authorCheng, VCCen_US
dc.contributor.authorYuen, KYen_US
dc.contributor.authorYam, WCen_US
dc.date.accessioned2012-08-08T08:51:46Z-
dc.date.available2012-08-08T08:51:46Z-
dc.date.issued2011en_US
dc.identifier.citationJournal of Antimicrobial Chemotherapy, 2011, v. 66 n. 4, p. 730-733en_US
dc.identifier.issn0305-7453en_US
dc.identifier.urihttp://hdl.handle.net/10722/157625-
dc.description.abstractObjectives: Ninety-six percent of rifampicin resistance in Mycobacterium tuberculosis was shown to be associated with mutations inside the 81 bp rifampicin resistance-determining region (RRDR) located in the centre of the rpoB gene. The detection of rifampicin resistance by targeting the RRDR failed to match with a resistant phenotype in 4% of all cases. Our study aims to identify the mutations outside the RRDR that are associated with rifampicin resistance in M. tuberculosis. Methods and results: Among 50 rifampicin-resistant and 20 rifampicin-susceptible clinical isolates of M. tuberculosis, 2 of the rifampicin-resistant isolates did not harbour any known mutations in the RRDR. Sequencing analysis of the whole rpoB gene identified two rare mutations, V146F and I572F. A molecular structure model based on Thermus thermophilus RpoB revealed that both these substituted amino acids are located in close proximity to the rifampicin-binding pocket of the β-subunit. Substitutions of simple amino acids for bulky ones are likely to affect the protein-drug interaction. Cloning and transformation of the mutated rpoB gene into wild-type Mycobacterium smegmatis and M. tuberculosis successfully elevated the MIC of rifampicin and conferred the rifampicin resistance phenotype. Conclusions: Our study showed that amino acid positions 146 and 572 are associated with rifampicin resistance in M. tuberculosis in addition to the RRDR. Molecular assays for identifying rifampicin-resistant M. tuberculosis might be improved in terms of accuracy by including these two positions. © The Author 2011. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.en_US
dc.languageengen_US
dc.publisherOxford University Press. The Journal's web site is located at http://jac.oxfordjournals.org/en_US
dc.relation.ispartofJournal of Antimicrobial Chemotherapyen_US
dc.subject.meshAmino Acid Substitution - Geneticsen_US
dc.subject.meshAntitubercular Agents - Pharmacologyen_US
dc.subject.meshBinding Sitesen_US
dc.subject.meshCloning, Molecularen_US
dc.subject.meshDna-Directed Rna Polymerases - Chemistry - Geneticsen_US
dc.subject.meshDrug Resistance, Bacterialen_US
dc.subject.meshHumansen_US
dc.subject.meshMutation, Missenseen_US
dc.subject.meshMycobacterium Smegmatis - Geneticsen_US
dc.subject.meshMycobacterium Tuberculosis - Drug Effects - Genetics - Isolation & Purificationen_US
dc.subject.meshRifampin - Pharmacologyen_US
dc.subject.meshThermus Thermophilus - Geneticsen_US
dc.subject.meshTuberculosis - Microbiologyen_US
dc.titleMutations outside the rifampicin resistance-determining region associated with rifampicin resistance in Mycobacterium tuberculosisen_US
dc.typeArticleen_US
dc.identifier.emailHo, PL:plho@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.authorityYuen, KY=rp00366en_US
dc.identifier.authorityYam, WC=rp00313en_US
dc.description.naturelink_to_OA_fulltexten_US
dc.identifier.doi10.1093/jac/dkq519en_US
dc.identifier.pmid21393153-
dc.identifier.scopuseid_2-s2.0-79952807087en_US
dc.identifier.hkuros209805-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79952807087&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume66en_US
dc.identifier.issue4en_US
dc.identifier.spage730en_US
dc.identifier.epage733en_US
dc.identifier.isiWOS:000288551300007-
dc.publisher.placeUnited Kingdomen_US
dc.identifier.scopusauthoridSiu, GKH=35485473100en_US
dc.identifier.scopusauthoridZhang, Y=35243647900en_US
dc.identifier.scopusauthoridLau, TCK=36981810500en_US
dc.identifier.scopusauthoridLau, RWT=36664762000en_US
dc.identifier.scopusauthoridHo, PL=7402211363en_US
dc.identifier.scopusauthoridYew, WW=7005934631en_US
dc.identifier.scopusauthoridTsui, SKW=7004961364en_US
dc.identifier.scopusauthoridCheng, VCC=23670479400en_US
dc.identifier.scopusauthoridYuen, KY=36078079100en_US
dc.identifier.scopusauthoridYam, WC=7004281720en_US
dc.identifier.citeulike9087363-

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