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dc.contributor.authorFeuerriegel, S.
dc.contributor.authorKoser, C. U.
dc.contributor.authorBau, D.
dc.contributor.authorRusch-Gerdes, S.
dc.contributor.authorSummers, D. K.
dc.contributor.authorArcher, John A.C.
dc.contributor.authorMarti-Renom, M. A.
dc.contributor.authorNiemann, S.
dc.date.accessioned2015-05-18T21:46:34Z
dc.date.available2015-05-18T21:46:34Z
dc.date.issued2011-09-19
dc.identifier.citationImpact of fgd1 and ddn Diversity in Mycobacterium tuberculosis Complex on In Vitro Susceptibility to PA-824 2011, 55 (12):5718 Antimicrobial Agents and Chemotherapy
dc.identifier.issn0066-4804
dc.identifier.issn1098-6596
dc.identifier.pmid21930879
dc.identifier.doi10.1128/AAC.05500-11
dc.identifier.urihttp://hdl.handle.net/10754/554101
dc.description.abstractPA-824 is a promising drug candidate for the treatment of tuberculosis (TB). It is in phase II clinical trials as part of the first newly designed regimen containing multiple novel antituberculosis drugs (PA-824 in combination with moxifloxacin and pyrazinamide). However, given that the genes involved in resistance against PA-824 are not fully conserved in the Mycobacterium tuberculosis complex (MTBC), this regimen might not be equally effective against different MTBC genotypes. To investigate this question, we sequenced two PA-824 resistance genes (fgd1 [Rv0407] and ddn [Rv3547]) in 65 MTBC strains representing major phylogenetic lineages. The MICs of representative strains were determined using the modified proportion method in the Bactec MGIT 960 system. Our analysis revealed single-nucleotide polymorphisms in both genes that were specific either for several genotypes or for individual strains, yet none of these mutations significantly affected the PA-824 MICs (≤0.25 μg/ml). These results were supported by in silico modeling of the mutations identified in Fgd1. In contrast, “Mycobacterium canettii” strains displayed a higher MIC of 8 μg/ml. In conclusion, we found a large genetic diversity in PA-824 resistance genes that did not lead to elevated PA-824 MICs. In contrast, M. canettii strains had MICs that were above the plasma concentrations of PA-824 documented so far in clinical trials. As M. canettii is also intrinsically resistant against pyrazinamide, new regimens containing PA-824 and pyrazinamide might not be effective in treating M. canettii infections. This finding has implications for the design of multiple ongoing clinical trials.
dc.publisherAmerican Society for Microbiology
dc.relation.urlhttp://aac.asm.org/cgi/doi/10.1128/AAC.05500-11
dc.rightsArchived with thanks to Antimicrobial Agents and Chemotherapy
dc.titleImpact of fgd1 and ddn Diversity in Mycobacterium tuberculosis Complex on In Vitro Susceptibility to PA-824
dc.typeArticle
dc.contributor.departmentComputational Bioscience Research Center (CBRC)
dc.identifier.journalAntimicrobial Agents and Chemotherapy
dc.identifier.pmcidPMC3232757
dc.eprint.versionPublisher's Version/PDF
dc.contributor.institutionMolecular Mycobacteriology, Research Center Borstel, Borstel, Germany
dc.contributor.institutionDepartment of Genetics, University of Cambridge, Cambridge, United Kingdom
dc.contributor.institutionStructural Genomics Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain
dc.contributor.institutionNational Reference Center for Mycobacteria, Research Center Borstel, Borstel, Germany
kaust.personArcher, John A.C.
refterms.dateFOA2018-06-13T10:05:26Z
dc.date.published-online2011-09-19
dc.date.published-print2011-12


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