MmpL3抑制剂的接种量依赖性杀菌活性。

Inoculum-dependent bactericidal activity of a MmpL3 inhibitor.

作者信息

Berube Bryan, Deshpande Aditi, Bhagwat Amala, Parish Tanya

机构信息

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

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

出版信息

bioRxiv. 2023 Feb 23:2023.02.22.529622. doi: 10.1101/2023.02.22.529622.

DOI:10.1101/2023.02.22.529622

PMID:36865226

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9980077/

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

吲哚羧酰胺是一类很有前景的抗结核药物，其作用靶点是海藻糖单霉菌酸酯（一种关键细胞壁成分）的输出蛋白MmpL3。我们测定了先导吲哚羧酰胺NITD-349的杀菌动力学，发现其对低密度培养物的杀菌速度很快，但杀菌活性取决于接种菌量。NITD-349与异烟肼（抑制霉菌酸合成）联合使用时杀菌率提高；这种联合用药即使在接种菌量较高时也能防止耐药突变体的出现。