Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Yale Center for Molecular Discovery, Yale West Campus, West Haven, CT 06516, USA.
Structure. 2022 Nov 3;30(11):1494-1507.e6. doi: 10.1016/j.str.2022.09.001. Epub 2022 Sep 26.
Fungal infections are the leading cause of mortality by eukaryotic pathogens, with an estimated 150 million severe life-threatening cases and 1.7 million deaths reported annually. The rapid emergence of multidrug-resistant fungal isolates highlights the urgent need for new drugs with new mechanisms of action. In fungi, pantothenate phosphorylation, catalyzed by PanK enzyme, is the first step in the utilization of pantothenic acid and coenzyme A biosynthesis. In all fungi sequenced so far, this enzyme is encoded by a single PanK gene. Here, we report the crystal structure of a fungal PanK alone as well as with high-affinity inhibitors from a single chemotype identified through a high-throughput chemical screen. Structural, biochemical, and functional analyses revealed mechanisms governing substrate and ligand binding, dimerization, and catalysis and helped identify new compounds that inhibit the growth of several Candida species. The data validate PanK as a promising target for antifungal drug development.
真菌感染是真核病原体导致死亡的主要原因，据估计，每年有 1.5 亿例严重危及生命的病例和 170 万人死亡。多药耐药真菌分离株的迅速出现凸显了对具有新作用机制的新药的迫切需求。在真菌中，泛酸磷酸化由 PanK 酶催化，是利用泛酸和辅酶 A 生物合成的第一步。在迄今为止测序的所有真菌中，该酶都由单个 PanK 基因编码。在这里，我们报告了真菌 PanK 单独以及通过高通量化学筛选从单一化学型中鉴定的高亲和力抑制剂的晶体结构。结构、生化和功能分析揭示了控制底物和配体结合、二聚化和催化的机制，并帮助鉴定了抑制几种念珠菌生长的新化合物。这些数据验证了 PanK 作为抗真菌药物开发有前途的靶标。
