Role of Alanine Racemase Mutations in Mycobacterium tuberculosis D-Cycloserine Resistance
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Peer-reviewed
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Abstract
Screening of more than 1,500 drug-resistant strains of Mycobacterium tuberculosis revealed evolutionary patterns characteristic of positive selection for three alanine racemase (Alr) mutations. We investigated these mutations using molecular modeling, in vitro MIC testing, as well as direct measurements of enzymatic activity, which demonstrated that these mutations likely confer resistance to D-cycloserine.
Description
Keywords
Mycobacterium tuberculosis, cycloserine, alanine racemase
Journal Title
Antimicrobial Agents and Chemotherapy
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Journal ISSN
0066-4804
1098-6596
1098-6596
Volume Title
61
Publisher
American Society for Microbiology
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Sponsorship
Wellcome Trust (098600/Z/12/Z)
This work was funded by the University of Otago, Health Research Council Explorer grant and Maurice Wilkins Centre. In addition, parts of this study were supported by the European Union PathoNgenTrace project (grant FP7-278864-2) and the German Center for Infection Research (DZIF). Further funds were received from Fundação para a Ciência e a Tecnologia, Portugal, through the grants UID/Multi/04413/2013 (to M.V. and D.M.), SFRH/BPD/100688/2014 (to D.M.), and SFRH/BPD/95406/2013 (to J.P.). F.C. was supported by the Wellcome Trust 201344/Z/16/Z. T.G.C. was funded by the Medical Research Council UK (grants MR/K000551/1, MR/M01360X/1, and MR/N010469/1). Further support was received the Indian Council of Medical Research, New Delhi and Health Innovation Challenge Fund (grants HICF-T5-342 and WT098600), a parallel funding partnership between the UK Department of Health and the Wellcome Trust. C.U.K. is a research associate at Wolfson College, Cambridge, UK. K.L.K., Y.N., and H.K.O.-R. have received funding for alanine racemase-related projects from L2 Diagnostics LLC, New Haven, CT. J.P., S.J.P., and C.U.K. have collaborated with Illumina, Inc. on a number of scientific projects. J.P. has received funding for travel and accommodation from Pacific Biosciences, Inc. and Illumina, Inc. S.J.P. has received funding for travel and accommodation from Illumina, Inc. C.U.K. is a consultant for the Foundation for Innovative New Diagnostics. The Bill & Melinda Gates Foundation and Janssen Pharmaceutica covered C.U.K.'s travel and accommodation to present at meetings. The European Society of Mycobacteriology awarded C.U.K. and M.M. the Gertrud Meissner Award, which is sponsored by Hain Lifescience.