Laboratório de Micologia, Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
Departamento de Microbiologia e Parasitologia, Instituto Biomédico, Universidade Federal Fluminense, Niterói, Brazil.
PLoS Negl Trop Dis. 2024 Oct 7;18(10):e0012586. doi: 10.1371/journal.pntd.0012586. eCollection 2024 Oct.
Auranofin is an approved anti-rheumatic drug that has a broad-range inhibitory action against several microorganisms, including human pathogenic fungi. The auranofin activity against Histoplasma capsulatum, the dimorphic fungus that causes histoplasmosis, has not been properly addressed. Since there are few therapeutic options for this life-threatening systemic mycosis, this study evaluated the effects of auranofin on H. capsulatum growth and expression of virulence factors.
METHODOLOGY/PRINCIPAL FINDINGS: Minimal inhibitory and fungicidal concentrations (MIC and MFC, respectively) of auranofin against 15 H. capsulatum strains with distinct genetic backgrounds were determined using the yeast form of the fungus and a microdilution protocol. Auranofin activity was also assessed on a macrophage model of infection and on a Tenebrio molitor invertebrate animal model. Expression of virulence-related genes was compared between auranofin treated and untreated H. capsulatum yeast cells using a quantitative PCR assay. Auranofin affected the growth of different strains of H. capsulatum, with MIC and MFC values ranging from 1.25 to 5.0 μM and from 2.5 to >10 μM, respectively. Auranofin was able to kill intracellular H. capsulatum yeast cells and conferred protection against the fungus in the experimental animal model of infection. Moreover, the expression of catalase A, HSP70, superoxide dismutase, thioredoxin reductase, serine proteinase, cytochrome C peroxidase, histone 2B, formamidase, metallopeptidase, Y20 and YPS3 proteins were reduced after six hours of auranofin treatment. CONCLUSIONS/SIGNIFICANCE: Auranofin is fungicidal against H. capsulatum and reduces the expression of several virulence-related genes, which makes this anti-rheumatic drug a good candidate for new medicines against histoplasmosis.
金诺芬是一种已批准的抗风湿药物，对多种微生物具有广谱抑制作用，包括人类致病性真菌。金诺芬对引起组织胞浆菌病的双相真菌荚膜组织胞浆菌的活性尚未得到妥善解决。由于这种危及生命的系统性真菌感染的治疗选择很少，因此本研究评估了金诺芬对荚膜组织胞浆菌生长和毒力因子表达的影响。
方法/主要发现：使用真菌的酵母形式和微量稀释方案，确定了金诺芬对具有不同遗传背景的 15 株荚膜组织胞浆菌的最小抑菌浓度（MIC）和最小杀菌浓度（MFC）。还在巨噬细胞感染模型和黄粉虫无脊椎动物模型上评估了金诺芬的活性。使用定量 PCR 测定法比较了金诺芬处理和未处理的荚膜组织胞浆菌酵母细胞中与毒力相关的基因表达。金诺芬影响不同株荚膜组织胞浆菌的生长，MIC 和 MFC 值分别为 1.25 至 5.0 μM 和 2.5 至> 10 μM。金诺芬能够杀死细胞内的荚膜组织胞浆菌酵母细胞，并在感染的实验动物模型中提供对真菌的保护。此外，过氧化氢酶 A、HSP70、超氧化物歧化酶、硫氧还蛋白还原酶、丝氨酸蛋白酶、细胞色素 C 过氧化物酶、组蛋白 2B、甲酰肽酶、金属肽酶、Y20 和 YPS3 蛋白的表达在金诺芬处理 6 小时后降低。结论/意义：金诺芬对荚膜组织胞浆菌具有杀菌作用，并降低了几种与毒力相关的基因的表达，这使得这种抗风湿药物成为治疗组织胞浆菌病的新药的良好候选药物。
