Role of alanine racemase mutations in Mycobacterium tuberculosis D-cycloserine resistance

Yoshio Nakatani; Helen K. Opel-Reading; Matthias Merker; Diana Machado; Sönke Andres; S. Siva Kumar; Danesh Moradigaravand; Francesc Coll; João Perdigão; Isabel Portugal; Thomas Schön; Dina Nair; K. R.Uma Devi; Thomas A. Kohl; Patrick Beckert; Taane G. Clark; Gugu Maphalala; Derrick Khumalo; Roland Diel; Kadri Klaos; Htin Lin Aung; Gregory M. Cook; Julian Parkhill; Sharon J. Peacock; Soumya Swaminathan; Miguel Viveiros; Stefan Niemann; Kurt L. Krause; Claudio U. Köser

doi:10.1128/AAC.01575-17

Role of alanine racemase mutations in Mycobacterium tuberculosis D-cycloserine resistance

Yoshio Nakatani, Helen K. Opel-Reading, Matthias Merker, Diana Machado, Sönke Andres, S. Siva Kumar, Danesh Moradigaravand, Francesc Coll, João Perdigão, Isabel Portugal, Thomas Schön, Dina Nair, K. R.Uma Devi, Thomas A. Kohl, Patrick Beckert, Taane G. Clark, Gugu Maphalala, Derrick Khumalo, Roland Diel, Kadri KlaosHtin Lin Aung, Gregory M. Cook, Julian Parkhill, Sharon J. Peacock, Soumya Swaminathan, Miguel Viveiros, Stefan Niemann, Kurt L. Krause^*, Claudio U. Köser

^*Corresponding author for this work

Clinic of Internal Medicine III - Pulmonology

34 Citations (Scopus)

Abstract

A 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.

Original language	English
Article number	e01575
Journal	Antimicrobial Agents and Chemotherapy
Volume	61
Issue number	12
ISSN	0066-4804
DOIs	https://doi.org/10.1128/AAC.01575-17
Publication status	Published - 12.2017

Funding

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). Fur- ther 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.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)

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Nakatani, Y., Opel-Reading, H. K., Merker, M., Machado, D., Andres, S., Kumar, S. S., Moradigaravand, D., Coll, F., Perdigão, J., Portugal, I., Schön, T., Nair, D., Devi, K. R. U., Kohl, T. A., Beckert, P., Clark, T. G., Maphalala, G., Khumalo, D., Diel, R., ... Köser, C. U. (2017). Role of alanine racemase mutations in Mycobacterium tuberculosis D-cycloserine resistance. Antimicrobial Agents and Chemotherapy, 61(12), Article e01575. https://doi.org/10.1128/AAC.01575-17

@article{c90ed11d850245a794b3edd81a47b13a,

title = "Role of alanine racemase mutations in Mycobacterium tuberculosis D-cycloserine resistance",

abstract = "A 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.",

author = "Yoshio Nakatani and Opel-Reading, \{Helen K.\} and Matthias Merker and Diana Machado and S{\"o}nke Andres and Kumar, \{S. Siva\} and Danesh Moradigaravand and Francesc Coll and Jo{\~a}o Perdig{\~a}o and Isabel Portugal and Thomas Sch{\"o}n and Dina Nair and Devi, \{K. R.Uma\} and Kohl, \{Thomas A.\} and Patrick Beckert and Clark, \{Taane G.\} and Gugu Maphalala and Derrick Khumalo and Roland Diel and Kadri Klaos and Aung, \{Htin Lin\} and Cook, \{Gregory M.\} and Julian Parkhill and Peacock, \{Sharon J.\} and Soumya Swaminathan and Miguel Viveiros and Stefan Niemann and Krause, \{Kurt L.\} and K{\"o}ser, \{Claudio U.\}",

note = "Funding Information: 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 Funda{\c c}{\~a}o para a Ci{\^e}ncia 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). Fur- Funding Information: ther 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. Funding Information: 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.{\textquoteright}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. Publisher Copyright: {\textcopyright} 2017 Nakatani et al. Copyright: Copyright 2017 Elsevier B.V., All rights reserved.",

year = "2017",

month = dec,

doi = "10.1128/AAC.01575-17",

language = "English",

volume = "61",

journal = "Antimicrobial Agents and Chemotherapy",

issn = "0066-4804",

publisher = "American Society for Microbiology",

number = "12",

}

Nakatani, Y, Opel-Reading, HK, Merker, M, Machado, D, Andres, S, Kumar, SS, Moradigaravand, D, Coll, F, Perdigão, J, Portugal, I, Schön, T, Nair, D, Devi, KRU, Kohl, TA, Beckert, P, Clark, TG, Maphalala, G, Khumalo, D, Diel, R, Klaos, K, Aung, HL, Cook, GM, Parkhill, J, Peacock, SJ, Swaminathan, S, Viveiros, M, Niemann, S, Krause, KL & Köser, CU 2017, 'Role of alanine racemase mutations in Mycobacterium tuberculosis D-cycloserine resistance', Antimicrobial Agents and Chemotherapy, vol. 61, no. 12, e01575. https://doi.org/10.1128/AAC.01575-17

TY - JOUR

T1 - Role of alanine racemase mutations in Mycobacterium tuberculosis D-cycloserine resistance

AU - Nakatani, Yoshio

AU - Opel-Reading, Helen K.

AU - Merker, Matthias

AU - Machado, Diana

AU - Andres, Sönke

AU - Kumar, S. Siva

AU - Moradigaravand, Danesh

AU - Coll, Francesc

AU - Perdigão, João

AU - Portugal, Isabel

AU - Schön, Thomas

AU - Nair, Dina

AU - Devi, K. R.Uma

AU - Kohl, Thomas A.

AU - Beckert, Patrick

AU - Clark, Taane G.

AU - Maphalala, Gugu

AU - Khumalo, Derrick

AU - Diel, Roland

AU - Klaos, Kadri

AU - Aung, Htin Lin

AU - Cook, Gregory M.

AU - Parkhill, Julian

AU - Peacock, Sharon J.

AU - Swaminathan, Soumya

AU - Viveiros, Miguel

AU - Niemann, Stefan

AU - Krause, Kurt L.

AU - Köser, Claudio U.

N1 - Funding Information: 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). Fur- Funding Information: ther 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. Funding Information: 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. Publisher Copyright: © 2017 Nakatani et al. Copyright: Copyright 2017 Elsevier B.V., All rights reserved.

PY - 2017/12

Y1 - 2017/12

N2 - A 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.

AB - A 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.

UR - https://www.scopus.com/pages/publications/85035036736

U2 - 10.1128/AAC.01575-17

DO - 10.1128/AAC.01575-17

M3 - Journal articles

C2 - 28971867

AN - SCOPUS:85035036736

SN - 0066-4804

VL - 61

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

IS - 12

M1 - e01575

ER -

Role of alanine racemase mutations in Mycobacterium tuberculosis D-cycloserine resistance

Abstract

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Research Areas and Centers

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