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首页> 外文期刊>BMC Microbiology >Growth inhibition and ultrastructural alterations induced by Δ24(25)-sterol methyltransferase inhibitors in Candida spp. isolates, including non-albicans organisms
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Growth inhibition and ultrastructural alterations induced by Δ24(25)-sterol methyltransferase inhibitors in Candida spp. isolates, including non-albicans organisms

机译：Δ24（25）-甾醇甲基转移酶抑制剂在念珠菌属中诱导的生长抑制和超微结构改变。分离株，包括非白色生物

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Background Although Candida species are commensal microorganisms, they can cause many invasive fungal infections. In addition, antifungal resistance can contribute to failure of treatment. The purpose of this study was to evaluate the antifungal activity of inhibitors of Δ24(25)-sterol methyltransferase (24-SMTI), 20-piperidin-2-yl-5α-pregnan-3β-20(R)-diol (AZA), and 24(R,S),25-epiminolanosterol (EIL), against clinical isolates of Candida spp., analysing the ultrastructural changes. Results AZA and EIL were found to be potent growth inhibitors of Candida spp. isolates. The median MIC50 was 0.5 μg.ml-1 for AZA and 2 μg.ml-1 for EIL, and the MIC90 was 2 μg.ml-1 for both compounds. All strains used in this study were susceptible to amphotericin B; however, some isolates were fluconazole- and itraconazole-resistant. Most of the azole-resistant isolates were Candida non-albicans (CNA) species, but several of them, such as C. guilliermondii, C. zeylanoides, and C. lipolytica, were susceptible to 24-SMTI, indicating a lack of cross-resistance. Reference strain C. krusei (ATCC 6258, FLC-resistant) was consistently susceptible to AZA, although not to EIL. The fungicidal activity of 24-SMTI was particularly high against CNA isolates. Treatment with sub-inhibitory concentrations of AZA and EIL induced several ultrastructural alterations, including changes in the cell-wall shape and thickness, a pronounced disconnection between the cell wall and cytoplasm with an electron-lucent zone between them, mitochondrial swelling, and the presence of electron-dense vacuoles. Fluorescence microscopy analyses indicated an accumulation of lipid bodies and alterations in the cell cycle of the yeasts. The selectivity of 24-SMTI for fungal cells versus mammalian cells was assessed by the sulforhodamine B viability assay. Conclusion Taken together, these results suggest that inhibition of 24-SMT may be a novel approach to control Candida spp. infections, including those caused by azole-resistant strains.
机译：背景技术尽管念珠菌属是共生微生物，但它们可引起许多侵入性真菌感染。另外，抗真菌抗性可能导致治疗失败。这项研究的目的是评估Δ 24（25）-甾醇甲基转移酶（24-SMTI），20-哌啶-2--2-基-5α-pregnan-3β-20抑制剂的抗真菌活性（R）-二醇（AZA）和24（R，S），25-表氨羊毛甾醇（EIL），针对念珠菌的临床分离株，分析其超微结构变化。结果发现AZA和EIL是念珠菌的有效生长抑制剂。隔离株。对于AZA，MIC 50 的中位数为0.5μg.ml -1 ;对于EIL，MIC的中位数MIC -1 ，而MIC 两种化合物的90 均为2μg.ml -1 。本研究中使用的所有菌株均对两性霉素B敏感;但是，某些分离株对氟康唑和伊曲康唑有抗药性。大多数对唑类具有抗药性的菌株均为非白色念珠菌（CNA）菌种，但其中的一些菌株，例如guilliermondii C.，zeylanoides和C. lipolytica，易患24-SMTI，表明缺乏交叉抵抗性。参考菌株克鲁氏梭菌（ATCC 6258，耐FLC）始终对AZA敏感，尽管对EIL不敏感。 24-SMTI对CNA分离株的杀真菌活性特别高。用亚抑制浓度的AZA和EIL进行治疗会引起几种超微结构改变，包括细胞壁形状和厚度的变化，细胞壁与细胞质之间的明显分离以及它们之间的电子透明区，线粒体肿胀以及存在电子致密液泡。荧光显微镜分析表明脂质体的积累和酵母细胞周期的改变。通过磺基罗丹明B生存力测定评估了24-SMTI对真菌细胞相对于哺乳动物细胞的选择性。结论综上所述，这些结果表明抑制24-SMT可能是控制念珠菌的一种新方法。感染，包括由耐唑菌株引起的感染。

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