Structural analyses of Candida albicans sterol 14α-demethylase complexed with azole drugs address the molecular basis of azole-mediated inhibition of fungal sterol biosynthesis
Structural analyses of Candida albicans sterol 14α-demethylase complexed with azole drugs address the molecular basis of azole-mediated inhibition of fungal sterol biosynthesis
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DOI：
10.1074/jbc.m117.778308
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发表时间：
2017-04-21
影响因子：
4.8
通讯作者：
Lepesheva, Galina I.
中科院分区：
文献类型：
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作者：
Hargrove, Tatiana Y.;Friggeri, Laura;Lepesheva, Galina I.
随着现代医学的一些进步（如癌症化疗，广泛接触抗生素和免疫抑制），机会性真菌病原体如白色念珠菌的发病率有所增加。这些病原体中的耐药性病例变得更加频繁，需要开发新药并更好地了解靶向酶。甾醇14 α-脱甲基酶（CYP 51）是真核细胞中甾醇生物合成所需的细胞色素P450酶，并且是用于管理真菌病原体的临床药物的主要靶点，但是对于合理药物设计重要的一些CYP 51关键特征仍然不清楚。我们报道了C.临床全身使用的抗真菌药物引起的白色念珠菌CYP 51（氟康唑、伏立康唑、酮康唑、伊曲康唑和泊沙康唑）和局部（咪康唑和克霉唑）和基于四唑的候选药物VT-1161（奥特塞唑：（R）-2-（2，4-二氟苯基）-1，1-二氟-3-（1H-四唑-1-基）-1-（5-（4（2，2，2-三氟乙氧基）苯基）吡啶-2-基）丙-2-醇）。在测试的化合物中，一线药物氟康唑是最弱的抑制剂，而泊沙康唑和VT-1161是最强的CYP 51抑制剂。测定了C.白念珠菌CYP 51与泊沙康唑和VT-1161的复合物，为这些药物的效力提供了分子机制，包括VT-1161对克鲁斯念珠菌和光滑念珠菌（对氟康唑具有内在耐药性的病原体）的活性。我们的比较结构分析概述了门特异性CYP 51功能，可以指导未来更有效的广谱抗真菌药的合理开发。
With some advances in modern medicine (such as cancer chemotherapy, broad exposure to antibiotics, and immunosuppression), the incidence of opportunistic fungal pathogens such as Candida albicans has increased. Cases of drug resistance among these pathogens have become more frequent, requiring the development of new drugs and a better understanding of the targeted enzymes. Sterol 14 alpha-demethylase (CYP51) is a cytochrome P450 enzyme required for biosynthesis of sterols in eukaryotic cells and is the major target of clinical drugs for managing fungal pathogens, but some of the CYP51 key features important for rational drug design have remained obscure. We report the catalytic properties, ligand-binding profiles, and inhibition of enzymatic activity of C. albicans CYP51 by clinical antifungal drugs that are used systemically (fluconazole, voriconazole, ketoconazole, itraconazole, and posaconazole) and topically (miconazole and clotrimazole) and by a tetrazolebased drug candidate, VT-1161 (oteseconazole: (R)-2-(2,4difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl) propan-2-ol). Among the compounds tested, the first-line drug fluconazole was the weakest inhibitor, whereas posaconazole and VT-1161 were the strongest CYP51 inhibitors. We determined the X-ray structures of C. albicans CYP51 complexes with posaconazole and VT-1161, providing a molecular mechanism for the potencies of these drugs, including the activity of VT-1161 against Candida krusei and Candida glabrata, pathogens that are intrinsically resistant to fluconazole. Our comparative structural analysis outlines phylum-specific CYP51 features that could direct future rational development of more efficient broadspectrum antifungals.