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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Impact of fgd1 and ddn diversity in Mycobacterium tuberculosis complex on in vitro susceptibility to PA-824
Antimicrobial Agents and Chemotherapy, Volume 55, No. 12, Year 2011
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Description
PA-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. Copyright © 2011, American Society for Microbiology. All Rights Reserved.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC3232757/bin/supp_55_12_5718__index.html
https://efashare.b-cdn.net/share/pmc/articles/PMC3232757/bin/supp_55.12.5718_SupplementaryComments.doc
https://efashare.b-cdn.net/share/pmc/articles/PMC3232757/bin/supp_55.12.5718_FigureS1.zip
Authors & Co-Authors
Feuerriegel, Silke
Germany, Borstel
Forschungszentrum Borstel - Zentrum Für Medizin Und Biowissenschaften
Köser, Claudio Umberto
United Kingdom, Cambridge
University of Cambridge
Baù, Davide
Spain, Valencia
Centro de Investigacion Principe Felipe
Rüsch-Gerdes, Sabine
Germany, Borstel
Forschungszentrum Borstel - Zentrum Für Medizin Und Biowissenschaften
Summers, David K.
United Kingdom, Cambridge
University of Cambridge
Archer, John A.C.
Saudi Arabia, Thuwal
King Abdullah University of Science and Technology
Marti-Renom, Marc A.
Spain, Valencia
Centro de Investigacion Principe Felipe
Niemann, Stefan
Germany, Borstel
Forschungszentrum Borstel - Zentrum Für Medizin Und Biowissenschaften
Statistics
Citations: 60
Authors: 8
Affiliations: 4
Identifiers
Doi:
10.1128/AAC.05500-11
ISSN:
00664804
e-ISSN:
10986596
Research Areas
Genetics And Genomics
Infectious Diseases