Role of Alanine Racemase Mutations in Mycobacterium tuberculosis D-Cycloserine Resistance

Peacock, Sharon; Koeser, Claudio; Parkhill, Julian; Nakatani, Y

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Authors

Peacock, Sharon

Koeser, Claudio

Parkhill, Julian

Nakatani, Y

Publication Date

2017-12

Journal Title

Antimicrobial Agents and Chemotherapy

ISSN

0066-4804

Publisher

American Society for Microbiology

Volume

Issue

Number

e01575-17

Type

Article

This Version

VoR

Metadata

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Citation

Peacock, S., Koeser, C., Parkhill, J., & Nakatani, Y. (2017). Role of Alanine Racemase Mutations in Mycobacterium tuberculosis D-Cycloserine Resistance. Antimicrobial Agents and Chemotherapy, 61 (12. e01575-17)https://doi.org/10.1128/AAC.01575-17

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.

Keywords

Mycobacterium tuberculosis, cycloserine, alanine racemase

Sponsorship

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.

Funder references

Wellcome Trust (098600/Z/12/Z)

Identifiers

External DOI: https://doi.org/10.1128/AAC.01575-17

This record's URL: https://www.repository.cam.ac.uk/handle/1810/269577

Rights

Attribution 4.0 International, Attribution 4.0 International

Licence URL: http://creativecommons.org/licenses/by/4.0/http://creativecommons.org/licenses/by/4.0/

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Except where otherwise noted, this item's licence is described as Attribution 4.0 International