Department of Biotransformation, Faculty of Biotechnology, University of Wroclaw, 50-383 Wroclaw, Poland.
Department of Industrial Microbiology and Biotechnology, Faculty of Biology and Environmental Protection, University of Łódź, 90-237 Lodz, Poland.
Int J Mol Sci. 2022 Jan 31;23(3):1631. doi: 10.3390/ijms23031631.
The opportunistic pathogen is responsible for life-threating infections in immunocompromised individuals. Azoles and polyenes are two of the most commonly used antifungals and target the ergosterol biosynthesis pathway or ergosterol itself. A limited number of clinically employed antifungals correspond to the development of resistance mechanisms. One resistance mechanism observed in clinical isolates of azole-resistant is the introduction of point mutations in the gene, which encodes a key enzyme (lanosterol 14-α-demethylase) on the ergosterol biosynthesis pathway. Here, we demonstrate that a point mutation K143R in ( ) contributes not only to azole resistance, but causes increased gene expression. Overexpression of results in increased ergosterol content and a significant reduction in plasma membrane fluidity. Simultaneously, the same point mutation caused cell wall remodeling. This could be facilitated by the unmasking of chitin and β-glucan on the fungal cell surface, which can lead to recognition of the highly immunogenic β-glucan, triggering a stronger immunological reaction. For the first time, we report that a frequently occurring azole-resistance strategy makes less susceptible to azole treatment while, at the same time, affects its cell wall architecture, potentially leading to exposure of the pathogen to a more effective host immune response.
机会性病原体是导致免疫功能低下个体生命威胁性感染的罪魁祸首。唑类药物和多烯类药物是两种最常用的抗真菌药物，它们作用于麦角固醇生物合成途径或麦角固醇本身。目前临床应用的抗真菌药物数量有限，这些药物对应的是耐药机制的发展。在临床分离的唑类耐药中观察到的一种耐药机制是在编码麦角固醇生物合成途径中的关键酶（羊毛甾醇 14-α-脱甲基酶）的 基因中引入点突变。在这里，我们证明 基因中的 K143R 点突变不仅有助于唑类耐药，而且导致基因表达增加。 过表达导致麦角固醇含量增加和质膜流动性显著降低。同时，相同的点突变导致细胞壁重塑。这可能是由于真菌细胞表面上的几丁质和β-葡聚糖的暴露，这可以导致对高度免疫原性的β-葡聚糖的识别，从而引发更强的免疫反应。我们首次报道，一种经常发生的唑类耐药策略使 对唑类药物治疗的敏感性降低，同时影响其细胞壁结构，可能导致病原体更容易受到更有效的宿主免疫反应的影响。
