PDF(Pubmed)
Abstract：
The opportunistic fungus Candida albicans is the leading cause of invasive candidiasis in immune-compromised individuals. Drugs from the echinocandin (ECN) class, including caspofungin, are used as a first line of therapy against invasive candidiasis. The only known mechanism of clinical resistance to ECNs is point mutations in the FKS1 gene, which encodes the drug target. However, many clinical isolates developed decreased ECN susceptibilities in the absence of resistance-associated FKS1 mutations. We have identified 15 C. albicans genes that contribute to decreased drug susceptibility. We explored the expression of these 15 genes in clinical isolates with different levels of ECN susceptibility. We found that these 15 genes are expressed in clinical isolates with or without FKS1 mutations, including those strains that are less susceptible to ECNs. In addition, FKS1 expression was increased in such less susceptible isolates compared to highly susceptible isolates. Similarities of gene expression patterns between isolates with decreased ECN susceptibilities in the absence of FKS1 mutations and clinically resistant isolates with mutations in FKS1 suggest that clinical isolates with decreased ECN susceptibilities may be a precursor to development of resistance.
摘要：
机会性真菌白色念珠菌是免疫受损个体中侵袭性念珠菌病的主要原因。棘白菌素（ECN）类药物，包括卡波芬金,被用作针对侵袭性念珠菌病的一线治疗。唯一已知的临床耐药机制是FKS1基因的点突变，编码药物靶标。然而,在没有耐药相关FKS1突变的情况下,许多临床分离株的ECN敏感性降低.我们已经鉴定了15个白色念珠菌基因，这些基因有助于降低药物敏感性。我们探索了这15个基因在具有不同ECN敏感性水平的临床分离株中的表达。我们发现这15个基因在有或没有FKS1突变的临床分离株中表达，包括那些对ECN不太敏感的菌株。此外,与高度易感的分离物相比,FKS1表达在此类较不易感的分离物中增加。在没有FKS1突变的情况下，ECN敏感性降低的分离株与FKS1突变的临床耐药分离株之间的基因表达模式的相似性表明，ECN敏感性降低的临床分离株可能是耐药性发展的前兆。
