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Antibiotics 2018, 7(1), 18; https://doi.org/10.3390/antibiotics7010018

Efflux Activity Differentially Modulates the Levels of Isoniazid and Rifampicin Resistance among Multidrug Resistant and Monoresistant Mycobacterium tuberculosis Strains

1
Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade NOVA de Lisboa, UNL, Lisboa 1349-008, Portugal
2
iMed.ULisboa, Instituto de Investigação do Medicamento, Faculdade de Farmácia, Universidade de Lisboa, Lisboa 1649-003, Portugal
3
P4T Group, University of Parma, Parco Area delle Scienze 27/A, Parma 43124, Italy
5
Núcleo de Pesquisa em Microbiologia Médica (NUPEMM), Faculdade de Medicina, Universidade Federal do Rio Grande, Rio Grande, Porto Alegre 96200-190, Brazil
4
Department of Food and Drug, University of Parma, Parco Area delle Scienze 27/A, Parma 43124, Italy
*
Author to whom correspondence should be addressed.
Received: 8 February 2018 / Revised: 28 February 2018 / Accepted: 1 March 2018 / Published: 3 March 2018
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Abstract

With the growing body of knowledge on the contribution of efflux activity to Mycobacterium tuberculosis drug resistance, increased attention has been given to the use of efflux inhibitors as adjuvants of tuberculosis therapy. Here, we investigated how efflux activity modulates the levels of efflux between monoresistant and multi- and extensively drug resistant (M/XDR) M. tuberculosis clinical isolates. The strains were characterized by antibiotic susceptibility testing in the presence/absence of efflux inhibitors, molecular typing, and genetic analysis of drug-resistance-associated genes. Efflux activity was quantified by real-time fluorometry. The results demonstrated that all the M. tuberculosis clinical strains, susceptible or resistant, presented a faster, rapid, and non-specific efflux-mediated short-term response to drugs. The synergism assays demonstrated that the efflux inhibitors were more effective in reducing the resistance levels in the M/XDR strains than in the monoresistant strains. This indicated that M/XDR strains presented a more prolonged response to drugs mediated by efflux compared to the monoresistant strains, but both maintain it as a long-term stress response. This work shows that efflux activity modulates the levels of drug resistance between monoresistant and M/XDR M. tuberculosis clinical strains, allowing the bacteria to survive in the presence of noxious compounds. View Full-Text
Keywords: efflux inhibitors; lineages; mutations; resistance levels; tuberculosis; verapamil efflux inhibitors; lineages; mutations; resistance levels; tuberculosis; verapamil
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Machado, D.; Perdigão, J.; Portugal, I.; Pieroni, M.; Silva, P.A.; Couto, I.; Viveiros, M. Efflux Activity Differentially Modulates the Levels of Isoniazid and Rifampicin Resistance among Multidrug Resistant and Monoresistant Mycobacterium tuberculosis Strains. Antibiotics 2018, 7, 18.

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