An Antifungal Combination Matrix Identifies a Rich Pool of Adjuvant Molecules that Enhance Drug Activity against Diverse Fungal Pathogens.
An Antifungal Combination Matrix Identifies a Rich Pool of Adjuvant Molecules that Enhance Drug Activity against Diverse Fungal Pathogens.
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DOI：
10.1016/j.celrep.2015.10.018
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发表时间：
2015-11-17
期刊：
影响因子：
8.8
通讯作者：
Wright GD
中科院分区：
文献类型：
--
作者：
Robbins N;Spitzer M;Yu T;Cerone RP;Averette AK;Bahn YS;Heitman J;Sheppard DC;Tyers M;Wright GD
迫切需要找到治疗真菌感染的新方法。通过将已知的抗真菌药物氟康唑、卡泊芬净、两性霉素B、特比奈芬、苯菌灵和克霉尼的亚致死浓度与不同真菌物种中的~3600种化合物相结合，我们产生了一个深层次的化学-化学相互作用储藏库，称为抗真菌组合矩阵(ACM)。对耐氟康唑的白色念珠菌分离株的后续药敏试验揭示了ACM组合能够在该临床菌株中增强氟康唑的作用。我们使用化学遗传学来阐明抗分枝杆菌药物氯法齐明的作用模式，这是一种与几种抗真菌药物协同作用的化合物，具有未见报道的抗真菌活性。氯法齐明诱导细胞膜应激，耐受需要Pkc1信号通路。对其他真菌病原体的进一步测试，包括烟曲霉，强调了氯法齐明作为一种联合药剂对多种真菌具有疗效。因此，ACM是一个丰富的化学组合储存库，具有治疗各种真菌病原体的潜力。
There is an urgent need to identify new treatments for fungal infections. By combining sub-lethal concentrations of the known antifungals fluconazole, caspofungin, amphotericin B, terbinafine, benomyl and cyprodinil with ~3600 compounds in diverse fungal species, we generated a deep reservoir of chemical-chemical interactions termed the Antifungal Combinations Matrix (ACM). Follow-up susceptibility testing against a fluconazole resistant isolate of C. albicans unveiled ACM combinations capable of potentiating fluconazole in this clinical strain. We used chemical genetics to elucidate the mode-of-action of the antimycobacterial drug clofazimine, a compound with unreported antifungal activity that synergized with several antifungals. Clofazimine induces a cell membrane stress for which the Pkc1 signaling pathway is required for tolerance. Further tests against additional fungal pathogens, including Aspergillus fumigatus, highlighted that clofazimine exhibits efficacy as a combination agent against multiple fungi. Thus, the ACM is a rich reservoir of chemical combinations with therapeutic potential against diverse fungal pathogens.