四氢吡啶衍生物作为分支杆菌属脓肿亚种的外排抑制剂。

Tetrahydropyridine derivative as efflux inhibitor in Mycobacterium abscessus.

机构信息

Núcleo de Pesquisa em Microbiologia Médica, Universidade Federal de Rio Grande, Rio Grande, RS, Brazil.

出版信息

J Glob Antimicrob Resist. 2019 Jun;17:296-299. doi: 10.1016/j.jgar.2018.12.020. Epub 2019 Jan 7.

DOI:10.1016/j.jgar.2018.12.020

PMID:30630106

Abstract

OBJECTIVES

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

The tetrahydropyridine derivative, NUNL02, is a promising adjuvant in the treatment of infections caused by M. abscessus.

摘要

目的

本研究旨在评估一种四氢吡啶衍生物（THP）作为一种潜在的外排机制抑制剂和调节剂，以改善通常在脓肿分枝杆菌（M. abscessus）组中观察到的高水平抗菌药物耐药性。

方法

使用脓肿分枝杆菌亚种脓肿（ATCC 19997）作为参考菌株，此外还有三个临床分离株：脓肿分枝杆菌亚种脓肿（AT 07），以及两个脓肿分枝杆菌亚种bolletii（AT 46 和 AT 52）。测定阿米卡星（AMI）、环丙沙星（CIP）、克拉霉素（CLA）、维拉帕米（VP）和 THP 衍生物（NUNL02）的最小抑菌浓度（MIC）。

结果

NUNL02对脓肿分枝杆菌具有活性；AMI 对 ATCC 19997 的 MIC 降低了 16 倍以上，CIP 对 AT 52 的 MIC 降低了 4 倍。当与 CLA 联合使用时，所有测试菌株的 MIC 均降低。此外，为了检测和量化外排机制的活性，评估了荧光底物溴化乙锭在存在和不存在 VP 和 NUNL02 时的细胞内积累动力学。发现 NUNL02 是一种比 VP 更有效的外排抑制剂，VP 是经典的抑制剂。