ArticleFrontiers in microbiology2015
Enhancement of antibiotic activity by efflux inhibitors against multidrug resistant Mycobacterium tuberculosis clinical isolates from Brazil.
Article in Frontiers in microbiology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 89 citations in OpenAlex.
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- Transfer learning predicts species-specific drug interactions in emerging pathogens.bioRxiv : the preprint server for biology · 2024Article
- Efflux pump effects on levofloxacin resistance inAntimicrobial agents and chemotherapy · 2024Article
- Combating multidrug-resistance inNAR molecular medicine · 2024Article
- The human proton pump inhibitors inhibitProceedings of the National Academy of Sciences of the United States of America · 2023Article
- C-1 Substituted isoquinolines potentiate the antimycobacterial activity of rifampicin and ethambutol.Frontiers in antibiotics · 2023Article
- Advances in the design of combination therapies for the treatment of tuberculosis.Expert opinion on drug discovery · 2023Review
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- Sodium Malonate Inhibits the AcrAB-TolC Multidrug Efflux Pump ofPathogens (Basel, Switzerland) · 2022Article
- Unraveling the mechanisms of intrinsic drug resistance inFrontiers in cellular and infection microbiology · 2022Review
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- Selective Inhibition of Coxiella burnetii Replication by the Steroid Hormone Progesterone.Infection and immunity · 2020Article
- The Contribution of Efflux Pumps inAntibiotics (Basel, Switzerland) · 2019Article
- Sodium Hyaluronate Nanocomposite Respirable Microparticles to Tackle Antibiotic Resistance with Potential Application in Treatment of Mycobacterial Pulmonary Infections.Pharmaceutics · 2019Article
- Comparison OfInfection and drug resistance · 2019Article
- Assessment of the Additional Value of Verapamil to a Moxifloxacin and Linezolid Combination Regimen in a Murine Tuberculosis Model.Antimicrobial agents and chemotherapy · 2018Article
- Verapamil Targets Membrane Energetics in Mycobacterium tuberculosis.Antimicrobial agents and chemotherapy · 2018Article
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Drug resistant tuberculosis continues to increase and new approaches for its treatment are necessary. The identification of M. tuberculosis clinical isolates presenting efflux as part of their resistant phenotype has a major impact in tuberculosis treatment. In this work, we used a checkerboard procedure combined with the tetrazolium microplate-based assay (TEMA) to study single combinations between antituberculosis drugs and efflux inhibitors (EIs) against multidrug resistant M. tuberculosis clinical isolates using the fully susceptible strain H37Rv as reference. Efflux activity was studied on a real-time basis by a fluorometric method that uses ethidium bromide as efflux substrate. Quantification of efflux pump genes mRNA transcriptional levels were performed by RT-qPCR. The fractional inhibitory concentrations (FIC) indicated synergistic activity for the interactions between isoniazid, rifampicin, amikacin, ofloxacin, and ethidium bromide plus the EIs verapamil, thioridazine and chlorpromazine. The FICs ranged from 0.25, indicating a four-fold reduction on the MICs, to 0.015, 64-fold reduction. The detection of active efflux by real-time fluorometry showed that all strains presented intrinsic efflux activity that contributes to the overall resistance which can be inhibited in the presence of the EIs. The quantification of the mRNA levels of the most important efflux pump genes on these strains shows that they are intrinsically predisposed to expel toxic compounds as the exposure to subinhibitory concentrations of antibiotics were not necessary to increase the pump mRNA levels when compared with the non-exposed counterpart. The results obtained in this study confirm that the intrinsic efflux activity contributes to the overall resistance in multidrug resistant clinical isolates of M. tuberculosis and that the inhibition of efflux pumps by the EIs can enhance the clinical effect of antibiotics that are their substrates.
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