Clofazimine Exposure In Vitro Selects Efflux Pump Mutants and Bedaquiline Resistance

Nabila Ismail; Remco P. H. Peters; Nazir A. Ismail; Shaheed V. Omar

doi:10.1128/AAC.02141-18

Clofazimine Exposure In Vitro Selects Efflux Pump Mutants and Bedaquiline Resistance

Nabila Ismail^*, Remco P. H. Peters, Nazir A. Ismail, Shaheed V. Omar

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Six in vitro clofazimine-resistant spontaneous mutants obtained from a wild-type or pyrazinamide-resistant ATCC reference strain were selected to evaluate bedaquiline cross-resistance. The reverse was conducted for bedaquiline mutants. All clofazimine mutants harboring an rv0678 mutation displayed phenotypic cross-resistance. We observed the same for rv0678 bedaquiline mutants; however, atpE bedaquiline mutants showed no phenotypic cross-resistance. This confirms that upfront clofazimine usage may impact subsequent bedaquiline use due to a shared efflux resistance pathway.

Original language	English
Article number	ARTN e02141-18
Number of pages	4
Journal	Antimicrobial Agents and Chemotherapy
Volume	63
Issue number	3
DOIs	https://doi.org/10.1128/AAC.02141-18
Publication status	Published - Mar 2019

Keywords

bedaquiline
clofazimine
cross-resistance
efflux pump mutants
MYCOBACTERIUM-TUBERCULOSIS
ATP SYNTHASE

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10.1128/AAC.02141-18

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title = "Clofazimine Exposure In Vitro Selects Efflux Pump Mutants and Bedaquiline Resistance",

abstract = "Six in vitro clofazimine-resistant spontaneous mutants obtained from a wild-type or pyrazinamide-resistant ATCC reference strain were selected to evaluate bedaquiline cross-resistance. The reverse was conducted for bedaquiline mutants. All clofazimine mutants harboring an rv0678 mutation displayed phenotypic cross-resistance. We observed the same for rv0678 bedaquiline mutants; however, atpE bedaquiline mutants showed no phenotypic cross-resistance. This confirms that upfront clofazimine usage may impact subsequent bedaquiline use due to a shared efflux resistance pathway.",

keywords = "bedaquiline, clofazimine, cross-resistance, efflux pump mutants, MYCOBACTERIUM-TUBERCULOSIS, ATP SYNTHASE",

author = "Nabila Ismail and Peters, {Remco P. H.} and Ismail, {Nazir A.} and Omar, {Shaheed V.}",

note = "Funding Information: N.I. was supported by the National Research Fund (SFH150723130071) and the University of Pretoria. This project was funded by the WHO Supranational Reference TB Laboratory, National Institute for Communicable Diseases, Johannesburg, South Africa, and by the National Health Laboratory Services (NHLS) Research Trust (grant 004_94640). We have no conflicts of interest to declare for this study. Publisher Copyright: {\textcopyright} 2019 American Society for Microbiology. All Rights Reserved.",

year = "2019",

month = mar,

doi = "10.1128/AAC.02141-18",

language = "English",

volume = "63",

journal = "Antimicrobial Agents and Chemotherapy",

issn = "0066-4804",

publisher = "American Society for Microbiology",

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T1 - Clofazimine Exposure In Vitro Selects Efflux Pump Mutants and Bedaquiline Resistance

AU - Ismail, Nabila

AU - Peters, Remco P. H.

AU - Ismail, Nazir A.

AU - Omar, Shaheed V.

N1 - Funding Information: N.I. was supported by the National Research Fund (SFH150723130071) and the University of Pretoria. This project was funded by the WHO Supranational Reference TB Laboratory, National Institute for Communicable Diseases, Johannesburg, South Africa, and by the National Health Laboratory Services (NHLS) Research Trust (grant 004_94640). We have no conflicts of interest to declare for this study. Publisher Copyright: © 2019 American Society for Microbiology. All Rights Reserved.

PY - 2019/3

Y1 - 2019/3

N2 - Six in vitro clofazimine-resistant spontaneous mutants obtained from a wild-type or pyrazinamide-resistant ATCC reference strain were selected to evaluate bedaquiline cross-resistance. The reverse was conducted for bedaquiline mutants. All clofazimine mutants harboring an rv0678 mutation displayed phenotypic cross-resistance. We observed the same for rv0678 bedaquiline mutants; however, atpE bedaquiline mutants showed no phenotypic cross-resistance. This confirms that upfront clofazimine usage may impact subsequent bedaquiline use due to a shared efflux resistance pathway.

AB - Six in vitro clofazimine-resistant spontaneous mutants obtained from a wild-type or pyrazinamide-resistant ATCC reference strain were selected to evaluate bedaquiline cross-resistance. The reverse was conducted for bedaquiline mutants. All clofazimine mutants harboring an rv0678 mutation displayed phenotypic cross-resistance. We observed the same for rv0678 bedaquiline mutants; however, atpE bedaquiline mutants showed no phenotypic cross-resistance. This confirms that upfront clofazimine usage may impact subsequent bedaquiline use due to a shared efflux resistance pathway.

KW - bedaquiline

KW - clofazimine

KW - cross-resistance

KW - efflux pump mutants

KW - MYCOBACTERIUM-TUBERCULOSIS

KW - ATP SYNTHASE

U2 - 10.1128/AAC.02141-18

DO - 10.1128/AAC.02141-18

M3 - Article

C2 - 30642938

SN - 0066-4804

VL - 63

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

IS - 3

M1 - ARTN e02141-18

ER -

Clofazimine Exposure In Vitro Selects Efflux Pump Mutants and Bedaquiline Resistance

Abstract

Keywords

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