Rao R Shyama Prasad, Pinto Larina, Shastry Rajesh P, Dakal Tikam Chand, Suravajhala Prashanth, Sashindran V K, Ghate Sudeep D
Center for Bioinformatics, NITTE deemed to be University, Mangaluru, 575018, India.
Central Research Laboratory, KS Hegde Medical Academy (KSHEMA), NITTE deemed to be University, Mangaluru, 575018, India.
Antonie Van Leeuwenhoek. 2025 Apr 17;118(5):68. doi: 10.1007/s10482-025-02080-1.
The emergence of azole-resistant Candida infections is a major concern. A key mechanism is the gain of resistance through amino acid substitutions in the sterol 14α-demethylase, the main target of azole drugs. While numerous resistant substitutions are known, the pattern of such substitutions remains unclear. We hypothesized that resistant substitutions occur disproportionately at azole-binding sites. We compiled 2222 instances of azole-resistant substitutions from the literature and performed extensive computational sequence analyses. Altogether, there were 169 known substitutions at 133 sites in sterol 14α-demethylases of seven Candida species, whereas C. albicans alone had 120 substitutions at 97 sites. Just 10 sites and 18 substitutions (such as Y132F/H, K143R, D116E, and G464S) accounted for 75% of the total instances. Only about 48% of the sites were present within previously recognized hotspot regions, while just 33% of the azole-interacting residues had known resistant substitutions, most of them with only a few instances. The literature data on azole-resistant substitutions in Candida appear to be highly biased, as a few substitutions, such as Y132F/H and K143R, were preferentially sought and reported with over 1,000 instances. Additionally, there were numerous reports of "resistant" substitutions in azole-susceptible Candida isolates. Our study provides new perspectives into azole resistance.
唑类耐药念珠菌感染的出现是一个主要问题。一个关键机制是通过甾醇14α-脱甲基酶（唑类药物的主要靶点）中的氨基酸取代获得耐药性。虽然已知有许多耐药性取代，但此类取代的模式仍不清楚。我们假设耐药性取代在唑类结合位点不成比例地发生。我们从文献中收集了2222例唑类耐药性取代实例，并进行了广泛的计算序列分析。七种念珠菌的甾醇14α-脱甲基酶共有133个位点发生了169个已知取代，而仅白色念珠菌就有97个位点发生了120个取代。仅10个位点和18个取代（如Y132F/H、K143R、D116E和G464S）占总实例的75%。只有约48%的位点位于先前识别的热点区域内，而只有33%的与唑类相互作用的残基有已知的耐药性取代，其中大多数只有少数实例。念珠菌中唑类耐药性取代的文献数据似乎存在高度偏差，因为少数取代，如Y132F/H和K143R，被优先寻找并报告了1000多个实例。此外，在对唑类敏感的念珠菌分离株中也有许多关于“耐药”取代的报道。我们的研究为唑类耐药性提供了新的视角。
