甘油醛3-磷酸脱氢酶
白色念珠菌
黄原酮
白色体
体内
生物化学
抗真菌药
对接(动物)
化学
热带假丝酵母
体外
生物
脱氢酶
酶
微生物学
立体化学
医学
生物技术
护理部
作者
Xingru Chen,Tao Zhou,Zhuo-Da Zhou,Zhan-Hong Fang,Kai‐Bo Wang,Chao Zhang,Ling‐Yi Kong,Ming‐Hua Yang
标识
DOI:10.1016/j.ijantimicag.2024.107172
摘要
This study aimed to discover novel antifungals targeting Candida albicans glyceraldehyde-3-phosphate dehydrogenase (CaGAPDH), have an insight into inhibitory mode, and provide evidence supporting CaGAPDH as a target for new antifungals. Virtual screening was utilized to discover inhibitors of CaGAPDH. The inhibitory effect on cellular GAPDH was evaluated by determining the levels of ATP, NAD, NADH, etc., as well as examining GAPDH mRNA and protein expression. The role of GAPDH inhibition in C. albicans was supported by drug affinity responsive target stability and overexpression experiments. The mechanism of CaGAPDH inhibition was elucidated by Michaelis-Menten enzyme kinetics and site-specific mutagenesis based on docking. Chemical synthesis was used to produce an improved candidate. Different sources of GAPDH were used to evaluate inhibitory selectivity across species. In vitro and in vivo antifungal tests, along with antibiofilm activity, were carried out to evaluate antifungal potential of GAPDH inhibitors. A natural xanthone was identified as the first competitive inhibitor of CaGAPDH. It demonstrated in vitro anti-C. albicans potential but also caused hemolysis. XP-W, a synthetic side-chain-optimized xanthone, demonstrated a better safety profile, exhibiting a 50-fold selectivity for CaGAPDH over human GAPDH. XP-W also exhibited potent antibiofilm activity and displayed broad-spectrum anti-Candida activities in vitro and in vivo, including multi-azole-resistant C. albicans. These results demonstrate for the first time that CaGAPDH is a valuable target for antifungal drug discovery, and XP-W provides a promising lead.
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