依赖菌量的 MmpL3 抑制剂杀菌活性。

Inoculum-dependent bactericidal activity of a MmpL3 inhibitor.

机构信息

Center for Global Infectious Disease, Seattle Children's Research Institute, Seattle, WA, USA.

TB Discovery Research, Infectious Disease Research Institute, Seattle, WA, USA.

出版信息

Microbiology (Reading). 2023 Jun;169(6). doi: 10.1099/mic.0.001345.

DOI:10.1099/mic.0.001345

PMID:37334886

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10333795/

Abstract

Indolcarboxamides are a promising series of anti-tubercular agents, which target MmpL3, the exporter of trehalose monomycolate, a key cell-wall component. We determined the kill kinetics of the lead indolcarboxamide NITD-349 and determined that while kill was rapid against low-density cultures, bactericidal activity was inoculum-dependent. A combination of NITD-349 with isoniazid (which inhibits mycolate synthesis) had an increased kill rate; this combination prevented the appearance of resistant mutants, even at higher inocula.

摘要

吲哚酰胺类化合物是一组很有前途的抗结核药物，它们的作用靶点是 MmpL3，该蛋白是海藻糖单胞壁酸的外排泵，而海藻糖单胞壁酸是细胞壁的一个关键组成部分。我们测定了先导吲哚酰胺化合物 NITD-349 的杀菌动力学，结果表明，尽管该药对低密度培养物具有快速杀菌作用，但杀菌活性依赖于接种物的数量。NITD-349 与异烟肼（抑制胞壁酸合成）联合使用具有更高的杀菌率；这种联合用药甚至在高接种量时也能防止耐药突变体的出现。