Common Biological Properties of Mycobacterium tuberculosis MmpL3 Inhibitors

IF 3.8 2区医学 Q2 CHEMISTRY, MEDICINAL

ACS Infectious Diseases Pub Date : 2025-08-19 DOI:10.1021/acsinfecdis.5c00394

Lauren Ames, Renee Allen, Helena I. M. Boshoff, Laura A. T. Cleghorn, Curtis A. Engelhart, Dirk Schnappinger and Tanya Parish*,

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Abstract

MmpL3 is a promising new target for antitubercular drugs, but the microbiological properties of MmpL3 inhibitors are not fully understood. We compared the activity and mode of action of 11 structurally diverse compound series that target MmpL3. We confirmed the activity was via MmpL3 using strains with differential expression of MmpL3. MmpL3 inhibitors had potent activity against replicating M. tuberculosis, with increased activity against intramacrophage bacilli and were rapidly bactericidal. MmpL3 inhibition induced cell wall stress concomitantly with a boost in the ATP levels in M. tuberculosis. Mutation in MmpL3 conferred resistance to all series at different levels. The molecules did not negatively impact membrane potential, pH homeostasis, or induce reactive oxygen species and were inactive against starved bacilli. Our study revealed common features related to the chemical inhibition of MmpL3, enabling the identification of off-target effects and highlighting the potential of such compounds as future drug candidates.

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结核分枝杆菌MmpL3抑制剂的常见生物学特性。

MmpL3是一种很有前景的抗结核药物新靶点，但MmpL3抑制剂的微生物学特性尚不完全清楚。我们比较了11种结构不同的靶向MmpL3的化合物系列的活性和作用方式。我们利用MmpL3差异表达的菌株证实了该活性是通过MmpL3产生的。MmpL3抑制剂对复制型结核分枝杆菌具有有效的活性，对巨噬杆菌的活性增加，并能快速杀菌。MmpL3抑制诱导结核分枝杆菌细胞壁应激，同时增加ATP水平。MmpL3突变对所有系列的不同程度产生抗性。这些分子不会对膜电位、pH稳态产生负面影响，也不会诱导活性氧，对饥饿杆菌无活性。我们的研究揭示了与MmpL3的化学抑制相关的共同特征，使鉴定脱靶效应成为可能，并突出了这些化合物作为未来候选药物的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Infectious Diseases CHEMISTRY, MEDICINALINFECTIOUS DISEASES&nb-INFECTIOUS DISEASES

CiteScore

9.70

自引率

3.80%

发文量

213

期刊介绍： ACS Infectious Diseases will be the first journal to highlight chemistry and its role in this multidisciplinary and collaborative research area. The journal will cover a diverse array of topics including, but not limited to: * Discovery and development of new antimicrobial agents — identified through target- or phenotypic-based approaches as well as compounds that induce synergy with antimicrobials. * Characterization and validation of drug target or pathways — use of single target and genome-wide knockdown and knockouts, biochemical studies, structural biology, new technologies to facilitate characterization and prioritization of potential drug targets. * Mechanism of drug resistance — fundamental research that advances our understanding of resistance; strategies to prevent resistance. * Mechanisms of action — use of genetic, metabolomic, and activity- and affinity-based protein profiling to elucidate the mechanism of action of clinical and experimental antimicrobial agents. * Host-pathogen interactions — tools for studying host-pathogen interactions, cellular biochemistry of hosts and pathogens, and molecular interactions of pathogens with host microbiota. * Small molecule vaccine adjuvants for infectious disease. * Viral and bacterial biochemistry and molecular biology.