Section of Infectious Diseases, Department of Medicine, Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA.
Departments of Molecular Genetics and Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH, USA.
Commun Biol. 2024 Jul 23;7(1):894. doi: 10.1038/s42003-024-06595-7.
Fungal infections, a leading cause of mortality among eukaryotic pathogens, pose a growing global health threat due to the rise of drug-resistant strains. New therapeutic strategies are urgently needed to combat this challenge. The PCA pathway for biosynthesis of Co-enzyme A (CoA) and Acetyl-CoA (AcCoA) from vitamin B5 (pantothenic acid) has been validated as an excellent target for the development of new antimicrobials against fungi and protozoa. The pathway regulates key cellular processes including metabolism of fatty acids, amino acids, sterols, and heme. In this study, we provide genetic evidence that disruption of the PCA pathway in Saccharomyces cerevisiae results in a significant alteration in the susceptibility of fungi to a wide range of xenobiotics, including clinically approved antifungal drugs through alteration of vacuolar morphology and drug detoxification. The drug potentiation mediated by genetic regulation of genes in the PCA pathway could be recapitulated using the pantazine analog PZ-2891 as well as the celecoxib derivative, AR-12 through inhibition of fungal AcCoA synthase activity. Collectively, the data validate the PCA pathway as a suitable target for enhancing the efficacy and safety of current antifungal therapies.
真菌感染是真核病原体死亡的主要原因，由于耐药菌株的出现，它对全球健康构成了越来越大的威胁。迫切需要新的治疗策略来应对这一挑战。从维生素 B5（泛酸）生物合成辅酶 A（CoA）和乙酰辅酶 A（AcCoA）的 PCA 途径已被验证为开发针对真菌和原生动物的新型抗菌药物的绝佳靶点。该途径调节包括脂肪酸、氨基酸、固醇和血红素代谢在内的关键细胞过程。在这项研究中，我们提供了遗传证据，表明破坏酿酒酵母中的 PCA 途径会导致真菌对广泛的外源性物质（包括临床批准的抗真菌药物）的敏感性发生重大变化，这是通过改变液泡形态和药物解毒来实现的。通过遗传调控 PCA 途径中的基因，可以使用 pantazine 类似物 PZ-2891 以及 celecoxib 衍生物 AR-12 模拟药物增效作用，这两种物质通过抑制真菌 AcCoA 合酶活性。总的来说，这些数据验证了 PCA 途径作为增强现有抗真菌疗法疗效和安全性的合适靶点。
