Targeting bedaquiline mycobacterial efflux pump to potentially enhance therapy in
Antitubercular Agents
/ pharmacology
Belgium
Cystic Fibrosis
/ complications
Diarylquinolines
/ pharmacology
Genotype
Humans
Membrane Transport Proteins
Microbial Sensitivity Tests
Mycobacterium Infections, Nontuberculous
/ drug therapy
Mycobacterium abscessus
/ classification
Reserpine
/ pharmacology
Sputum
/ microbiology
Verapamil
/ pharmacology
Bedaquiline
Mycobacterium abscessus
efflux pump
mycobacteria
Journal
International journal of mycobacteriology
ISSN: 2212-554X
Titre abrégé: Int J Mycobacteriol
Pays: India
ID NLM: 101615660
Informations de publication
Date de publication:
Historique:
entrez:
1
6
2020
pubmed:
1
6
2020
medline:
10
4
2021
Statut:
ppublish
Résumé
Mycobacterium abscessus is notorious for being intrinsically resistant to most antibiotics. Antibiotic efflux is one of the mechanisms used by M. abscessus to pump out antibiotics from their cells. Inhibiting efflux pumps (EPs) can be an attractive strategy to enhance the activity of drugs. The objective of this study is to determine the activity of EP inhibitors (EPIs) to enhance the efficacy of the new drug bedaquiline against M. abscessus clinical isolates. A total of 31 phenotypically and genotypically identified M. abscessus subsp. abscessus, M. abscesss subsp. massiliense, and M. abscessus subsp. bolletii clinical isolates were studied. The contribution of EPs was determined by investigating the minimum inhibitory concentration (MIC) levels of bedaquiline reduction in the absence and presence of EPIs verapamil and reserpine using the resazurin microtiter assay. The observed bedaquiline MIC reduction by verapamil was observed in 100% isolates and by reserpine in 54.8% isolates. Bedaquiline MIC was 4-32-fold using verapamil with M. abscessus subsp. bolletii showing the highest fold change and between 2- and 4-fold using reserpine. The results obtained in this study confirm that bedaquiline MIC decreased in the presence of EPIs verapamil and reserpine in clinical isolates of M. abscessus. Verapamil was the most effective EPI. As shown in previous studies, verapamil may have clinical potential as adjunctive therapy to enhance the effect of bedaquiline.
Sections du résumé
Background
Mycobacterium abscessus is notorious for being intrinsically resistant to most antibiotics. Antibiotic efflux is one of the mechanisms used by M. abscessus to pump out antibiotics from their cells. Inhibiting efflux pumps (EPs) can be an attractive strategy to enhance the activity of drugs. The objective of this study is to determine the activity of EP inhibitors (EPIs) to enhance the efficacy of the new drug bedaquiline against M. abscessus clinical isolates.
Methods
A total of 31 phenotypically and genotypically identified M. abscessus subsp. abscessus, M. abscesss subsp. massiliense, and M. abscessus subsp. bolletii clinical isolates were studied. The contribution of EPs was determined by investigating the minimum inhibitory concentration (MIC) levels of bedaquiline reduction in the absence and presence of EPIs verapamil and reserpine using the resazurin microtiter assay.
Results
The observed bedaquiline MIC reduction by verapamil was observed in 100% isolates and by reserpine in 54.8% isolates. Bedaquiline MIC was 4-32-fold using verapamil with M. abscessus subsp. bolletii showing the highest fold change and between 2- and 4-fold using reserpine.
Conclusions
The results obtained in this study confirm that bedaquiline MIC decreased in the presence of EPIs verapamil and reserpine in clinical isolates of M. abscessus. Verapamil was the most effective EPI. As shown in previous studies, verapamil may have clinical potential as adjunctive therapy to enhance the effect of bedaquiline.
Identifiants
pubmed: 32474492
pii: IntJMycobacteriol_2020_9_1_71_280139
doi: 10.4103/ijmy.ijmy_181_19
doi:
Substances chimiques
Antitubercular Agents
0
Diarylquinolines
0
Membrane Transport Proteins
0
bedaquiline
78846I289Y
Reserpine
8B1QWR724A
Verapamil
CJ0O37KU29
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
71-75Déclaration de conflit d'intérêts
None