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 & 9 others Htin Lin Aung, Gregory M Cook, Julian Parkhill, Sharon J Peacock, Soumya Swaminathan, Miguel Viveiros, Stefan Niemann, Kurt L Krause, Claudio U Köser

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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.

Original languageEnglish
JournalAntimicrobial Agents and Chemotherapy
Volume61
Issue number12
DOIs
Publication statusE-pub ahead of print - 2 Oct 2017

Fingerprint

Alanine Racemase
Cycloserine
Mycobacterium tuberculosis
Mutation
Pharmaceutical Preparations

Keywords

  • Alanine racemase
  • Cycloserine
  • Mycobacterium tuberculosis complex Mycobacterium bovis Bovine tuberculosis Real-time PCR

Cite this

Nakatani, Yoshio ; Opel-Reading, Helen K ; Merker, Matthias ; Machado, Diana ; Andres, Sönke ; Kumar, S Siva ; Moradigaravand, Danesh ; Coll, Francesc ; Perdigão, João ; Portugal, Isabel ; Schön, Thomas ; Nair, Dina ; Devi, K R Uma ; Kohl, Thomas A ; Beckert, Patrick ; Clark, Taane G ; Maphalala, Gugu ; Khumalo, Derrick ; Diel, Roland ; Klaos, Kadri ; Aung, Htin Lin ; Cook, Gregory M ; Parkhill, Julian ; Peacock, Sharon J ; Swaminathan, Soumya ; Viveiros, Miguel ; Niemann, Stefan ; Krause, Kurt L ; Köser, Claudio U. / Role of alanine racemase mutations in Mycobacterium tuberculosis D-cycloserine resistance. In: Antimicrobial Agents and Chemotherapy. 2017 ; Vol. 61, No. 12.
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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.",
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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. https://doi.org/10.1128/AAC.01575-17

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

In: Antimicrobial Agents and Chemotherapy, Vol. 61, No. 12, 02.10.2017.

Research output: Contribution to journalArticle

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 - Copyright © 2017 Nakatani et al.

PY - 2017/10/2

Y1 - 2017/10/2

N2 - 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 - 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.

KW - Alanine racemase

KW - Cycloserine

KW - Mycobacterium tuberculosis complex Mycobacterium bovis Bovine tuberculosis Real-time PCR

U2 - 10.1128/AAC.01575-17

DO - 10.1128/AAC.01575-17

M3 - Article

VL - 61

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 0066-4804

IS - 12

ER -