Naturally-Occurring Polymorphisms in QcrB Are Responsible for Resistance to Telacebec in Mycobacterium abscessus

Ria Sorayah; Malathy Sony Subramanian Manimekalai; Sung Jae Shin; Won Jung Koh; Gerhard Grüber; Kevin Pethe

doi:10.1021/acsinfecdis.9b00322

Naturally-Occurring Polymorphisms in QcrB Are Responsible for Resistance to Telacebec in Mycobacterium abscessus

Ria Sorayah, Malathy Sony Subramanian Manimekalai, Sung Jae Shin, Won Jung Koh, Gerhard Grüber, Kevin Pethe

Department of Microbiology

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

6 Citations (Scopus)

Abstract

Mycobacterium abscessus (M. abscessus) is a rapidly growing nontuberculous mycobacteria that is quickly emerging as a global health concern. M. abscessus pulmonary infections are frequently intractable due to the high intrinsic resistance to most antibiotics. Therefore, there is an urgent need to discover effective pharmacological options for M. abscessus infections. In this study, the potency of the antituberculosis drug Telacebec (Q203) was evaluated against M. abscessus. Q203 is a clinical-stage drug candidate targeting the subunit QcrB of the cytochrome bc₁:aa₃ terminal oxidase. We demonstrated that the presence of four naturally-occurring polymorphisms in the M. abscessus QcrB is responsible for the high resistance of the bacterium to Q203. Genetics reversion of the four polymorphisms sensitized M. abscessus to Q203. While this study highlights the limitation of a direct drug repurposing approach of Q203 and related drugs for M. abscessus infections, it reveals that the M. abscessus cytochrome bc₁:aa₃ respiratory branch is sensitive to chemical inhibition.

Original language	English
Pages (from-to)	2055-2060
Number of pages	6
Journal	ACS Infectious Diseases
Volume	5
Issue number	12
DOIs	https://doi.org/10.1021/acsinfecdis.9b00322
Publication status	Published - 2019 Dec 13

Bibliographical note

Funding Information:
This research is supported by the Lee Kong Chian School of Medicine, Nanyang Technological University Start-Up Grant (awarded to K.P.). R.S. is supported by a scholarship from NTU Institute for Health Technologies (HealthTech NTU), Interdisciplinary Graduate Programme, Nanyang Technological University.

Publisher Copyright:
© 2019 American Chemical Society.

All Science Journal Classification (ASJC) codes

Infectious Diseases

UN SDGs

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

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10.1021/acsinfecdis.9b00322

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title = "Naturally-Occurring Polymorphisms in QcrB Are Responsible for Resistance to Telacebec in Mycobacterium abscessus",

abstract = "Mycobacterium abscessus (M. abscessus) is a rapidly growing nontuberculous mycobacteria that is quickly emerging as a global health concern. M. abscessus pulmonary infections are frequently intractable due to the high intrinsic resistance to most antibiotics. Therefore, there is an urgent need to discover effective pharmacological options for M. abscessus infections. In this study, the potency of the antituberculosis drug Telacebec (Q203) was evaluated against M. abscessus. Q203 is a clinical-stage drug candidate targeting the subunit QcrB of the cytochrome bc1:aa3 terminal oxidase. We demonstrated that the presence of four naturally-occurring polymorphisms in the M. abscessus QcrB is responsible for the high resistance of the bacterium to Q203. Genetics reversion of the four polymorphisms sensitized M. abscessus to Q203. While this study highlights the limitation of a direct drug repurposing approach of Q203 and related drugs for M. abscessus infections, it reveals that the M. abscessus cytochrome bc1:aa3 respiratory branch is sensitive to chemical inhibition.",

author = "Ria Sorayah and Manimekalai, {Malathy Sony Subramanian} and Shin, {Sung Jae} and Koh, {Won Jung} and Gerhard Gr{\"u}ber and Kevin Pethe",

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AU - Koh, Won Jung

AU - Grüber, Gerhard

AU - Pethe, Kevin

N1 - Funding Information: This research is supported by the Lee Kong Chian School of Medicine, Nanyang Technological University Start-Up Grant (awarded to K.P.). R.S. is supported by a scholarship from NTU Institute for Health Technologies (HealthTech NTU), Interdisciplinary Graduate Programme, Nanyang Technological University. Publisher Copyright: © 2019 American Chemical Society.

PY - 2019/12/13

Y1 - 2019/12/13

N2 - Mycobacterium abscessus (M. abscessus) is a rapidly growing nontuberculous mycobacteria that is quickly emerging as a global health concern. M. abscessus pulmonary infections are frequently intractable due to the high intrinsic resistance to most antibiotics. Therefore, there is an urgent need to discover effective pharmacological options for M. abscessus infections. In this study, the potency of the antituberculosis drug Telacebec (Q203) was evaluated against M. abscessus. Q203 is a clinical-stage drug candidate targeting the subunit QcrB of the cytochrome bc1:aa3 terminal oxidase. We demonstrated that the presence of four naturally-occurring polymorphisms in the M. abscessus QcrB is responsible for the high resistance of the bacterium to Q203. Genetics reversion of the four polymorphisms sensitized M. abscessus to Q203. While this study highlights the limitation of a direct drug repurposing approach of Q203 and related drugs for M. abscessus infections, it reveals that the M. abscessus cytochrome bc1:aa3 respiratory branch is sensitive to chemical inhibition.

AB - Mycobacterium abscessus (M. abscessus) is a rapidly growing nontuberculous mycobacteria that is quickly emerging as a global health concern. M. abscessus pulmonary infections are frequently intractable due to the high intrinsic resistance to most antibiotics. Therefore, there is an urgent need to discover effective pharmacological options for M. abscessus infections. In this study, the potency of the antituberculosis drug Telacebec (Q203) was evaluated against M. abscessus. Q203 is a clinical-stage drug candidate targeting the subunit QcrB of the cytochrome bc1:aa3 terminal oxidase. We demonstrated that the presence of four naturally-occurring polymorphisms in the M. abscessus QcrB is responsible for the high resistance of the bacterium to Q203. Genetics reversion of the four polymorphisms sensitized M. abscessus to Q203. While this study highlights the limitation of a direct drug repurposing approach of Q203 and related drugs for M. abscessus infections, it reveals that the M. abscessus cytochrome bc1:aa3 respiratory branch is sensitive to chemical inhibition.

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Naturally-Occurring Polymorphisms in QcrB Are Responsible for Resistance to Telacebec in Mycobacterium abscessus

Abstract

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