In silico and in vitro evaluation of tetrahydropyridine compounds as efflux inhibitors in Mycobacterium abscessus

I. B. Ramis, Júlia S. Vianna, L. Silva Junior, Andrea von Groll, Daniela F. Ramos, Nilo Zanatta, Miguel Viveiros, Pedro E.Almeida da Silva

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

Herein, we evaluated tetrahydropyridine (THP) compounds (NUNM) as antimicrobials and inhibitors of the efflux mechanism in M. abscessus. subsp. abscessus. The modulation factor (MF) of efflux inhibitors was calculated from the minimum inhibitory concentrations (MICs) of amikacin (AMI), ciprofloxacin (CIP) and clarithromycin (CLA) in the absence and presence of subinhibitory concentrations of the NUNM compounds and canonical inhibitors carbonyl cyanide m-chlorophenyl hydrazone (CCCP) and verapamil (VP). The kinetics of the intracellular accumulation of the fluorimetric substrate ethidium bromide (EtBr) was evaluated and calculated by the relative final fluorescence (RFF). In addition, molecular modeling simulations for the MmpL5 and Tap efflux transporters with ligands (CLA, NUNM, CCCP, VP and EtBr) were performed to better understand the efflux mechanism. We highlight the NUNM01 compound because it reduced the MICs of AMI, CIP and CLA by 4-, 4- and 16-fold, respectively, had the highest effect on EtBr accumulation (RFF = 3.1) and showed a significant in silico affinity for the evaluated proteins in docking simulations. Based on the analyses performed in vitro and in silico, we propose that NUNM01 is a potential pharmacophore candidate for the development of a therapeutic adjuvant for M. abscessus infections.

Original languageEnglish
Article number101853
Pages (from-to)101853-101865
Number of pages12
JournalTuberculosis
Volume118
DOIs
Publication statusPublished - 1 Sep 2019

Keywords

  • Drug resistance
  • Efflux
  • Molecular modeling
  • Mycobacteria
  • Tetrahydropyridine

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