School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China.
The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), Shanghai 200433, China.
J Med Chem. 2023 Sep 14;66(17):11893-11904. doi: 10.1021/acs.jmedchem.3c00488. Epub 2023 Aug 16.
has emerged as an important opportunistic pathogen of invasive candidiasis due to increasing drug resistance. Targeting Pdr1-KIX interactions with small molecules represents a potential strategy for treating drug-resistant candidiasis. However, effective Pdr1-KIX inhibitors are rather limited, hindering the validation of target druggability. Here, new Pdr1-KIX inhibitors were designed and assayed. Particularly, compound possessed a new chemical scaffold and exhibited potent KIX binding affinity, leading to enhanced synergistic efficacy with fluconazole to treat resistant infection (FICI = 0.28). Compound acted by inhibiting the efflux pump and down-regulating resistance-associated genes through blocking the Pdr1-KIX interaction. Compound exhibited excellent and antifungal potency in combination with fluconazole against azole-resistant . It also had direct antifungal effect to treat infection, suggesting new mechanisms of action independent of Pdr1-KIX inhibition. Therefore, compound represents a promising lead compound for antifungal drug development.
由于耐药性的增加，已成为侵袭性念珠菌病的一种重要机会致病菌。针对 Pdr1-KIX 相互作用的小分子代表了治疗耐药性念珠菌病的一种潜在策略。然而，有效的 Pdr1-KIX 抑制剂相当有限，阻碍了靶标可药性的验证。在这里，设计并检测了新的 Pdr1-KIX 抑制剂。特别是，化合物 具有新的化学结构骨架，表现出很强的 KIX 结合亲和力，与氟康唑联合使用可增强治疗耐药 感染的协同效果（FICI = 0.28）。化合物 通过抑制外排泵并通过阻断 Pdr1-KIX 相互作用下调耐药相关基因来发挥作用。化合物 与氟康唑联合使用对唑类耐药 的 表现出优异的 和抗真菌效力。它还具有直接的抗真菌作用，可治疗 感染，提示其具有独立于 Pdr1-KIX 抑制的新作用机制。因此，化合物 代表了一种有前途的抗真菌药物开发的先导化合物。
