Chemosensitization prevents tolerance of Aspergillus fumigatus to antimycotic drugs
Chemosensitization prevents tolerance of Aspergillus fumigatus to antimycotic drugs
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DOI：
10.1016/j.bbrc.2008.05.030
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发表时间：
2008-07-18
影响因子：
3.1
通讯作者：
May, Gregory
中科院分区：
文献类型：
--
作者：
Kim, Jong;Campbell, Bruce;May, Gregory
人类病原真菌对抗真菌药物的耐受性是一个新出现的医学问题。我们展示了对细胞壁干扰抗真菌药物具有耐受性的人类曲霉病病原体烟曲霉菌株如何通过天然化合物的化学增敏而变得敏感。烟曲霉丝裂原激活蛋白激酶 (MAPK) 突变体 sukA Delta 对这些药物的耐受性表明渗透/氧化应激 MAPK 途径参与维持细胞壁完整性。利用酿酒酵母的缺失突变体，我们首先鉴定出百里香酚和 2,3-二羟基苯甲醛 (2,3-D) 作为针对细胞壁的有效化学增敏剂。然后，我们使用这些化学增敏剂作为商业抗真菌药物的增效剂，对抗烟曲霉的耐受菌株。百里酚是两性霉素 B、氟康唑或酮康唑的特别有效的化学增敏剂。讨论了天然、安全的化学增敏剂在人类真菌病的抗真菌化疗中作为联合治疗的替代方案的潜在用途。由爱思唯尔公司出版
Tolerance of human pathogenic fungi to antifungal drugs is an emerging medical problem. We show how strains of the causative agent of human aspergillosis, Aspergillus fumigatus, tolerant to cell wall-interfering antimycotic drugs become susceptible through chemosensitization by natural compounds. Tolerance of the A. fumigatus mitogen-activated protein kinase (MAPK) mutant, sukA Delta, to these drugs indicates the osmotic/oxidative stress MAPK pathway is involved in maintaining cell wall integrity. Using deletion mutants of the yeast, Saccharomyces cerevisiae, we first identified thymol and 2,3-dihydroxybenzaldehyde (2,3-D) as potent chemosensitizing agents that target the cell wall. We then used these chemosensitizing agents to act as synergists to commercial antifungal drugs against tolerant strains of A. fumigatus. Thymol was an especially potent chemosensitizing agent for amphotericin B, fluconazole or ketoconazole. The potential use of natural, safe chemosensitizing agents in antifungal chemotherapy of human mycoses as an alternative to combination therapy is discussed. Published by Elsevier Inc.