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.
Highlights
Species belonging to the Mycobacterium abscessus complex are responsible for pulmonary and extrapulmonary infections affecting mostly the skin and soft-tissues [1,2]
We have investigated the role of increased efflux pump gene mRNA levels and the increased efflux activity in six M. abscessus strains when exposed to sub-inhibitory concentrations of clarithromycin as one of the mechanisms contributing to inducible macrolide resistance
The results obtained in this study provide evidence that efflux activity is an intrinsic characteristic of M. abscessus clinical strains and is directly involved in clarithromycin resistance
Summary
Species belonging to the Mycobacterium abscessus complex are responsible for pulmonary and extrapulmonary infections affecting mostly the skin and soft-tissues [1,2]. These species are estimated to account for 5–20% of all nontuberculous mycobacteria (NTM) infections worldwide [3]. M. abscessus complex comprises three subspecies: M. abscessus subsp. The pattern of drug susceptibility differs according to the subspecies stressing the importance of their differentiation among the complex, as they will respond differently to the therapeutic regimen [1,6,7,8]. M. abscessus subspecies differ on their antimicrobial susceptibilities, to macrolides, the first-line antibiotic for the treatment of these infections [10]
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