Tetrahydropyridine derivative as efflux inhibitor in Mycobacterium abscessus

• Published in: Journal of global antimicrobial resistance. Vol. 17; pp. 296 - 299
• Main Authors: Vianna, Júlia S., Ramis, Ivy B., Bierhals, Dienefer, von Groll, Andrea, Ramos, Daniela F., Zanatta, Nilo, Lourenço, Maria Cristina, Viveiros, Miguel, Almeida da Silva, Pedro E.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.06.2019
• Subjects: Amikacin - pharmacology; Anti-Bacterial Agents - pharmacology; Biological Transport - drug effects; Ciprofloxacin - pharmacology; Clarithromycin - pharmacology; Efflux pump; Humans; Microbial Sensitivity Tests; Mycobacteria; Mycobacterium abscessus - drug effects; Pyrrolidines - chemistry; Pyrrolidines - pharmacology; Tetrahydropyridine; Verapamil - pharmacology; Tetrahydropyridine; Mycobacteria; Efflux pump
• ISSN: 2213-7165; 2213-7173
• DOI: 10.1016/j.jgar.2018.12.020

•Studies described the role of efflux mechanisms in resistance of Mycobacterium spp.•Efflux inhibitor in therapy can reduce the intrinsic and acquired resistance.•Molecules such as tetrahydropyridines can be candidates for efflux inhibitors in bacteria.•Tetrahydropyridine derivative, NUNL02, was active on the inhibition of ethidium bromide efflux against Mycobacterium abscessus.•Tetrahydropyridine derivative, NUNL2, is a promising adjuvant in the treatment of infections caused by Mycobacterium abscessus. This study aimed to evaluate a tetrahydropyridine derivative (THP) as a potential inhibitor of the efflux mechanism and modulator of the high level of antimicrobial resistance usually observed in members of the Mycobacterium abscessus (M. abscessus) group. The strain M. abscessus subsp. abscessus (ATCC 19997) was used as reference, in addition to three clinical isolates: M. abscessus subsp. abscessus (AT 07), and two M. abscessus subsp. bolletii (AT 46 and AT 52). The minimum inhibitory concentration (MIC) of amikacin (AMI), ciprofloxacin (CIP), clarithromycin (CLA), verapamil (VP), and THP derivative (NUNL02) was determined. The NUNL02 showed activity against M. abscessus; the MIC of AMI against ATCC 19997 was reduced more than 16-fold, and the MIC of CIP against AT 52 was reduced four-fold. When combined with CLA, the MIC was reduced against all tested strains. In addition, to detect and quantify the activity of the efflux mechanism, the intracellular accumulation kinetics of the fluorometric substrate ethidium bromide in the presence and absence of VP and NUNL02 were evaluated. The NUNL02 was found to be a more effective efflux inhibitor than VP, which is the classical inhibitor. The tetrahydropyridine derivative, NUNL02, is a promising adjuvant in the treatment of infections caused by M. abscessus.