Marichal P, Vanden Bossche H
Department of Comparative Biochemistry, Janssen Research Foundation, Beerse, Belgium.
Acta Biochim Pol. 1995;42(4):509-16.
Until the late eighties, clinical resistance to azole antifungals was a rare phenomenon. Only a few cases of resistance to ketoconazole were found in patients with chronic mucocutaneous candidiasis (CMC). The spread of AIDS and the widespread prophylactic and therapeutic use of the hydrophilic azole compound fluconazole resulted both in the selection and induction of resistant strains and in a shift in the nature of the infecting organisms. Most azole antifungals such as itraconazole, ketoconazole and fluconazole are active against a variety of fungal diseases. However, the concentration needed to inhibit growth is dependent on the nature of the infecting species. Mucor spp., e.g., are almost insensitive to present available azole compounds and can be regarded as intrinsically resistant to azole treatment. Physiochemical features, such as the hydrophobicity and pKa, of a given azole, define whether or not it will be active or cross-resistant against a given species. Fluconazole is almost inactive against Candida krusei and Aspergillus fumigatus, whereas the lipophilic itraconazole is active against these species. A third type of resistance is acquired or induced resistance. This is the most controversial type because, even within a given species, organisms may differ in their response to the same azole. For these strains, convincing evidence can only be obtained when there is a genotypically related strain, which does not show resistance. In a limited number of biochemical or molecular biological studies the mechanisms of resistance have been investigated at the molecular level. These studies show that resistance can occur when there is an insufficient intracellular content of the azole. This can be due to impermeability problems, inactivated uptake systems or, and more likely, the presence of active multidrug resistance gene products of the P-glycoprotein type. Alteration or overexpression of the target for azole antifungals, the cytochrome P450-dependent 14 alpha-demethylase, also induces resistance. The nature and amount of the accumulating sterols also are of great importance for azole-induced growth inhibition. This may explain why mutations in other enzymes of the ergosterol biosynthesis pathway, e.g. the delta 5-6 desaturase, can contribute to azole resistance.
直到八十年代后期，临床上对唑类抗真菌药产生耐药性还是一种罕见现象。在慢性黏膜皮肤念珠菌病（CMC）患者中仅发现少数对酮康唑耐药的病例。艾滋病的蔓延以及亲水性唑类化合物氟康唑的广泛预防性和治疗性使用，既导致了耐药菌株的选择和诱导，也使感染病原体的性质发生了变化。大多数唑类抗真菌药，如伊曲康唑、酮康唑和氟康唑，对多种真菌疾病都有活性。然而，抑制生长所需的浓度取决于感染菌种的性质。例如，毛霉属对现有的唑类化合物几乎不敏感，可被视为对唑类治疗具有固有耐药性。特定唑类的物理化学特性，如疏水性和pKa，决定了它对特定菌种是否有活性或交叉耐药性。氟康唑对克柔念珠菌和烟曲霉几乎无活性，而亲脂性的伊曲康唑对这些菌种有活性。第三种耐药类型是获得性或诱导性耐药。这是最具争议的类型，因为即使在同一菌种内，不同生物体对同一种唑类的反应也可能不同。对于这些菌株，只有当存在一个基因相关但不显示耐药性的菌株时，才能获得有说服力的证据。在有限的一些生化或分子生物学研究中，已经在分子水平上研究了耐药机制。这些研究表明，当唑类在细胞内的含量不足时，就会产生耐药性。这可能是由于通透性问题、摄取系统失活，或者更可能是由于存在P-糖蛋白类型的活性多药耐药基因产物。唑类抗真菌药的靶点细胞色素P450依赖性14α-脱甲基酶的改变或过度表达也会诱导耐药性。积累的甾醇的性质和数量对于唑类诱导的生长抑制也非常重要。这也许可以解释为什么麦角固醇生物合成途径中其他酶（如Δ5-6去饱和酶）的突变会导致唑类耐药。
