Impact of fgd1 and ddn Diversity in Mycobacterium tuberculosis Complex on In Vitro Susceptibility to PA-824
Koser, C. U.
Summers, D. K.
Archer, John A.C.
Marti-Renom, M. A.
KAUST DepartmentComputational Bioscience Research Center (CBRC)
Permanent link to this recordhttp://hdl.handle.net/10754/554101
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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.
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
PublisherAmerican Society for Microbiology
PubMed Central IDPMC3232757
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