SQ109对多种真菌的广谱活性及其作用机制研究

IF 3.8 2区医学 Q2 CHEMISTRY, MEDICINAL

ACS Infectious Diseases Pub Date : 2025-05-14 DOI:10.1021/acsinfecdis.5c0021010.1021/acsinfecdis.5c00210

Satish R. Malwal, Rocio Garcia-Rubio, Milena Kordalewska, Hoja Patterson, Chi Zhang, Jorge D. Calderin, Ruijie Zhou, Akanksha M. Pandey, Erika Shor, David S. Perlin, Nathan P. Wiederhold, Luis Ostrosky-Zeichner, Rutilio Fratti, Carol Nacy and Eric Oldfield*,

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引用次数: 0

摘要

研究了结核药物SQ109对白色念珠菌、金黄色念珠菌、光秃念珠菌、吉列蒙念珠菌、kefyr念珠菌、krusei念珠菌、lusitaniae念珠菌、副结核念珠菌、热带念珠菌、新型隐球菌、根霉、毛霉、镰刀菌、球虫、荚膜组织原体和烟曲霉等16种病原菌的抑菌活性。MIC值变化很大（125 ng/mL至>；64 μg/mL），但在许多情况下，我们发现有希望的（MIC ~ 4 μg/mL）活性以及MFC/MIC比值为~ 2。SQ109代谢物无活性。12个SQ109类似物对酿酒酵母的活性与原胞解偶联活性相关，表明其靶向线粒体，这与抑制ROS物种积累的药物可以挽救生长抑制的观察结果一致。SQ109破坏酿酒酵母液泡中的H+/Ca2+稳态，与匹伐他汀有协同作用（FICI ~ 0.26），表明参与了类异戊二烯生物合成途径的抑制。因此，SQ109是一种具有多靶点活性的潜在抗真菌药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Broad-Spectrum Activity and Mechanisms of Action of SQ109 on a Variety of Fungi

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Broad-Spectrum Activity and Mechanisms of Action of SQ109 on a Variety of Fungi

We investigated the activity of the tuberculosis drug SQ109 against 16 fungal pathogens: Candida albicans, C. auris, C. glabrata, C. guilliermondi, C. kefyr, C. krusei, C. lusitaniae, C. parapsilosis, C. tropicalis, Cryptococcus neoformans, Rhizopus spp., Mucor spp., Fusarium spp., Coccidioides spp., Histoplasma capsulatum and Aspergillus fumigatus. MIC values varied widely (125 ng/mL to >64 μg/mL) but in many cases we found promising (MIC ∼ 4 μg/mL) activity as well as MFC/MIC ratios of ∼ 2. SQ109 metabolites were inactive. The activity of 12 analogs of SQ109 against Saccharomyces cerevisiae correlated with protonophore uncoupling activity, suggesting mitochondrial targeting, consistent with the observation that growth inhibition was rescued by agents which inhibit ROS species accumulation. SQ109 disrupted H⁺/Ca²⁺ homeostasis in S. cerevisiae vacuoles, and there was synergy (FICI ∼ 0.26) with pitavastatin, indicating involvement of isoprenoid biosynthesis pathway inhibition. SQ109 is, therefore, a potential antifungal agent with multitarget activity.

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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.