The contribution of efflux pumps in Mycobacterium abscessus complex resistance to Clarithromycin

Júlia S Vianna; Diana Machado; Ivy B Ramis; Fábia P Silva; Dienefer V Bierhals; Michael Andrés Abril; Andrea von Groll; Daniela F Ramos; Maria Cristina S Lourenço; Miguel Viveiros; Pedro E Almeida da Silva

doi:10.3390/antibiotics8030153

The contribution of efflux pumps in Mycobacterium abscessus complex resistance to Clarithromycin

Júlia S Vianna, Diana Machado, Ivy B Ramis, Fábia P Silva, Dienefer V Bierhals, Michael Andrés Abril, Andrea von Groll, Daniela F Ramos, Maria Cristina S Lourenço, Miguel Viveiros, Pedro E Almeida da Silva

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Abstract

The basis of drug resistance in Mycobacterium abscessus is still poorly understood. Nevertheless, as seen in other microorganisms, the efflux of antimicrobials may also play a role in M. abscessus drug resistance. Here, we investigated the role of efflux pumps in clarithromycin resistance using nine clinical isolates of M. abscessus complex belonging to the T28 erm(41) sequevar responsible for the inducible resistance to clarithromycin. The strains were characterized by drug susceptibility testing in the presence/absence of the efflux inhibitor verapamil and by genetic analysis of drug-resistance-associated genes. Efflux activity was quantified by real-time fluorometry. Efflux pump gene expression was studied by RT-qPCR upon exposure to clarithromycin. Verapamil increased the susceptibility to clarithromycin from 4- to ≥64-fold. The efflux pump genes MAB_3142 and MAB_1409 were found consistently overexpressed. The results obtained demonstrate that the T28 erm(41) polymorphism is not the sole cause of the inducible clarithromycin resistance in M.abscessus subsp. abscessus or bolletii with efflux activity providing a strong contribution to clarithromycin resistance. These data highlight the need for further studies on M. abscessus efflux response to antimicrobial stress in order to implement more effective therapeutic regimens and guidance in the development of new drugs against these bacteria.

Original language	English
Article number	153
Pages (from-to)	153-168
Number of pages	15
Journal	Antibiotics
Volume	8
Issue number	3
DOIs	https://doi.org/10.3390/antibiotics8030153
Publication status	Published - 18 Sept 2019

Keywords

Efflux inhibitors
Efflux pumps
Erm(41
Mutations
Mycobacteria
Verapamil

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

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The Contribution of Efflux Pumps in MycobacteriumFinal published version, 692 KBLicence: CC BY

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title = "The contribution of efflux pumps in Mycobacterium abscessus complex resistance to Clarithromycin",

abstract = "The basis of drug resistance in Mycobacterium abscessus is still poorly understood. Nevertheless, as seen in other microorganisms, the efflux of antimicrobials may also play a role in M. abscessus drug resistance. Here, we investigated the role of efflux pumps in clarithromycin resistance using nine clinical isolates of M. abscessus complex belonging to the T28 erm(41) sequevar responsible for the inducible resistance to clarithromycin. The strains were characterized by drug susceptibility testing in the presence/absence of the efflux inhibitor verapamil and by genetic analysis of drug-resistance-associated genes. Efflux activity was quantified by real-time fluorometry. Efflux pump gene expression was studied by RT-qPCR upon exposure to clarithromycin. Verapamil increased the susceptibility to clarithromycin from 4- to ≥64-fold. The efflux pump genes MAB_3142 and MAB_1409 were found consistently overexpressed. The results obtained demonstrate that the T28 erm(41) polymorphism is not the sole cause of the inducible clarithromycin resistance in M.abscessus subsp. abscessus or bolletii with efflux activity providing a strong contribution to clarithromycin resistance. These data highlight the need for further studies on M. abscessus efflux response to antimicrobial stress in order to implement more effective therapeutic regimens and guidance in the development of new drugs against these bacteria.",

keywords = "Efflux inhibitors, Efflux pumps, Erm(41, Mutations, Mycobacteria, Verapamil",

author = "Vianna, {J{\'u}lia S} and Diana Machado and Ramis, {Ivy B} and Silva, {F{\'a}bia P} and Bierhals, {Dienefer V} and Abril, {Michael Andr{\'e}s} and {von Groll}, Andrea and Ramos, {Daniela F} and Louren{\c c}o, {Maria Cristina S} and Miguel Viveiros and {da Silva}, {Pedro E Almeida}",

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T1 - The contribution of efflux pumps in Mycobacterium abscessus complex resistance to Clarithromycin

AU - Vianna, Júlia S

AU - Machado, Diana

AU - Ramis, Ivy B

AU - Silva, Fábia P

AU - Bierhals, Dienefer V

AU - Abril, Michael Andrés

AU - von Groll, Andrea

AU - Ramos, Daniela F

AU - Lourenço, Maria Cristina S

AU - Viveiros, Miguel

AU - da Silva, Pedro E Almeida

PY - 2019/9/18

Y1 - 2019/9/18

N2 - The basis of drug resistance in Mycobacterium abscessus is still poorly understood. Nevertheless, as seen in other microorganisms, the efflux of antimicrobials may also play a role in M. abscessus drug resistance. Here, we investigated the role of efflux pumps in clarithromycin resistance using nine clinical isolates of M. abscessus complex belonging to the T28 erm(41) sequevar responsible for the inducible resistance to clarithromycin. The strains were characterized by drug susceptibility testing in the presence/absence of the efflux inhibitor verapamil and by genetic analysis of drug-resistance-associated genes. Efflux activity was quantified by real-time fluorometry. Efflux pump gene expression was studied by RT-qPCR upon exposure to clarithromycin. Verapamil increased the susceptibility to clarithromycin from 4- to ≥64-fold. The efflux pump genes MAB_3142 and MAB_1409 were found consistently overexpressed. The results obtained demonstrate that the T28 erm(41) polymorphism is not the sole cause of the inducible clarithromycin resistance in M.abscessus subsp. abscessus or bolletii with efflux activity providing a strong contribution to clarithromycin resistance. These data highlight the need for further studies on M. abscessus efflux response to antimicrobial stress in order to implement more effective therapeutic regimens and guidance in the development of new drugs against these bacteria.

AB - The basis of drug resistance in Mycobacterium abscessus is still poorly understood. Nevertheless, as seen in other microorganisms, the efflux of antimicrobials may also play a role in M. abscessus drug resistance. Here, we investigated the role of efflux pumps in clarithromycin resistance using nine clinical isolates of M. abscessus complex belonging to the T28 erm(41) sequevar responsible for the inducible resistance to clarithromycin. The strains were characterized by drug susceptibility testing in the presence/absence of the efflux inhibitor verapamil and by genetic analysis of drug-resistance-associated genes. Efflux activity was quantified by real-time fluorometry. Efflux pump gene expression was studied by RT-qPCR upon exposure to clarithromycin. Verapamil increased the susceptibility to clarithromycin from 4- to ≥64-fold. The efflux pump genes MAB_3142 and MAB_1409 were found consistently overexpressed. The results obtained demonstrate that the T28 erm(41) polymorphism is not the sole cause of the inducible clarithromycin resistance in M.abscessus subsp. abscessus or bolletii with efflux activity providing a strong contribution to clarithromycin resistance. These data highlight the need for further studies on M. abscessus efflux response to antimicrobial stress in order to implement more effective therapeutic regimens and guidance in the development of new drugs against these bacteria.

KW - Efflux inhibitors

KW - Efflux pumps

KW - Erm(41

KW - Mutations

KW - Mycobacteria

KW - Verapamil

UR - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784190/

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DO - 10.3390/antibiotics8030153

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SN - 2079-6382

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EP - 168

JO - Antibiotics

JF - Antibiotics

IS - 3

M1 - 153

ER -

The contribution of efflux pumps in Mycobacterium abscessus complex resistance to Clarithromycin

Abstract

Keywords

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