Discovery of Pyrazolone Carbothioamide Derivatives as Inhibitors of the Pdr1-KIX Interaction for Combinational Treatment of Azole-Resistant Candidiasis.
Discovery of Pyrazolone Carbothioamide Derivatives as Inhibitors of the Pdr1-KIX Interaction for Combinational Treatment of Azole-Resistant Candidiasis.
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DOI：
10.1021/acs.jmedchem.3c00488
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发表时间：
2023-08
影响因子：
7.3
通讯作者：
Qingwen Wang;Jie Tu;Wanzhen Yang;Tingting Liang;Na Liu;C. Sheng
中科院分区：
文献类型：
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作者：
Qingwen Wang;Jie Tu;Wanzhen Yang;Tingting Liang;Na Liu;C. Sheng
光滑假丝酵母菌耐药性的增加已成为侵袭性念珠菌病的重要条件致病菌。靶向Pdr 1-KIX与小分子的相互作用代表了治疗耐药念珠菌病的潜在策略。然而，有效的Pdr 1-KIX抑制剂是相当有限的，阻碍了目标可药用性的验证。在此，设计并测定了新的Pdr 1-KIX抑制剂。特别地，化合物B8具有新的化学支架并表现出有效的KIX结合亲和力，导致与氟康唑治疗耐药C.光滑感染（FICI = 0.28）。化合物B8通过抑制外排泵并通过阻断Pdr 1-KIX相互作用下调抗性相关基因而起作用。化合物B8与氟康唑联用对唑类耐药念珠菌表现出良好的体外和体内抗真菌活性。光滑的对C. glabrata感染，提示新的作用机制独立于Pdr 1-KIX抑制。因此，化合物B8代表了抗真菌药物开发的有希望的先导化合物。
Candida glabrata 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 B8 possessed a new chemical scaffold and exhibited potent KIX binding affinity, leading to enhanced synergistic efficacy with fluconazole to treat resistant C. glabrata infection (FICI = 0.28). Compound B8 acted by inhibiting the efflux pump and down-regulating resistance-associated genes through blocking the Pdr1-KIX interaction. Compound B8 exhibited excellent in vitro and in vivo antifungal potency in combination with fluconazole against azole-resistant C. glabrata. It also had direct antifungal effect to treat C. glabrata infection, suggesting new mechanisms of action independent of Pdr1-KIX inhibition. Therefore, compound B8 represents a promising lead compound for antifungal drug development.