Disulfiram is a potent modulator of multidrug transporter Cdr1p of Candida albicans
Disulfiram is a potent modulator of multidrug transporter Cdr1p of Candida albicans
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DOI：
10.1016/j.bbrc.2004.07.151
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发表时间：
2004-09-17
影响因子：
3.1
通讯作者：
Ambudkar, SV
中科院分区：
文献类型：
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作者：
Shukla, S;Sauna, ZE;Ambudkar, SV
为了寻找有效治疗念珠菌病的新药，我们检测了用于治疗酒精中毒的药物双硫兰作为念珠菌多药转运体Cdr1p的潜在调节剂的作用。我们发现双硫兰抑制了Cdr1p对寡霉素敏感的ATPase活性，2.5 mM二硫苏糖醇逆转了这种抑制。双硫兰对Cdr1p的光亲和类似物([α-P-32]8-叠氮基ATP；IC_(50)=0.76 um)和药物底物([H-3]叠氮多宾和[I-125]碘芳基氮杂咪唑；IC_(50)类似于12 um)与Cdr1p的结合均有浓度依赖性的抑制作用，提示它既能与Cdr1p结合，又能与Cdr1p的底物结合部位(S)结合。此外，无毒浓度的双硫兰(1um)增加了表达Cdr1p的酿酒酵母细胞对抗真菌药物(氟康唑、咪康唑、制霉菌素和放线菌素)的敏感性。总而言之，这些结果表明，双硫兰通过与转运蛋白的ATP和底物结合位点相互作用来逆转Cdr1p介导的耐药性，并可能用于抗真菌治疗。由爱思唯尔公司出版。
To find novel drugs for effective antifungal therapy in candidiasis, we examined disulfiram, a drug used for the treatment of alcoholism, for its role as a potential modulator of Candida multidrug transporter Cdr1p. We show that disulfiram inhibits the oligomycin-sensitive ATPase activity of Cdr1p and 2.5 mM dithiothreitol reverses this inhibition. Disulfiram inhibited the binding of photoaffinity analogs of both ATP ([alpha-P-32]8-azidoATP; IC50 = 0.76 muM) and drug-substrates ([H-3]azidopine and [I-125]iodoarylazidoprazosin; IC50 similar to 12 muM) to Cdr1p in a concentration-dependent manner, suggesting that it can interact with both ATP and substrate-binding site(s) of Cdr1p. Furthermore, a non-toxic concentration of disulfiram (1 muM) increased the sensitivity of Cdr1p expressing Saccharomyces cerevisiae cells to antifungal agents (fluconazole, miconazole, nystatin, and cycloheximide). Collectively these results demonstrate that disulfiram reverses Cdr1p-mediated drug resistance by interaction with both ATP and substrate-binding sites of the transporter and may be useful for antifungal therapy. Published by Elsevier Inc.