Paul Sanjoy, Moye-Rowley W Scott
Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa Iowa City, IA, USA.
Front Physiol. 2014 Apr 16;5:143. doi: 10.3389/fphys.2014.00143. eCollection 2014.
A critical risk to the continued success of antifungal chemotherapy is the acquisition of resistance; a risk exacerbated by the few classes of effective antifungal drugs. Predictably, as the use of these drugs increases in the clinic, more resistant organisms can be isolated from patients. A particularly problematic form of drug resistance that routinely emerges in the major fungal pathogens is known as multidrug resistance. Multidrug resistance refers to the simultaneous acquisition of tolerance to a range of drugs via a limited or even single genetic change. This review will focus on recent progress in understanding pathways of multidrug resistance in fungi including those of most medical relevance. Analyses of multidrug resistance in Saccharomyces cerevisiae have provided the most detailed outline of multidrug resistance in a eukaryotic microorganism. Multidrug resistant isolates of S. cerevisiae typically result from changes in the activity of a pair of related transcription factors that in turn elicit overproduction of several target genes. Chief among these is the ATP-binding cassette (ABC)-encoding gene PDR5. Interestingly, in the medically important Candida species, very similar pathways are involved in acquisition of multidrug resistance. In both C. albicans and C. glabrata, changes in the activity of transcriptional activator proteins elicits overproduction of a protein closely related to S. cerevisiae Pdr5 called Cdr1. The major filamentous fungal pathogen, Aspergillus fumigatus, was previously thought to acquire resistance to azole compounds (the principal antifungal drug class) via alterations in the azole drug target-encoding gene cyp51A. More recent data indicate that pathways in addition to changes in the cyp51A gene are important determinants in A. fumigatus azole resistance. We will discuss findings that suggest azole resistance in A. fumigatus and Candida species may share more mechanistic similarities than previously thought.
抗真菌化疗持续取得成功的一个关键风险是产生耐药性；由于有效的抗真菌药物种类较少，这一风险进一步加剧。可以预见，随着这些药物在临床上的使用增加，从患者身上分离出的耐药微生物会更多。在主要真菌病原体中经常出现的一种特别成问题的耐药形式被称为多药耐药性。多药耐药性是指通过有限甚至单一的基因变化同时获得对一系列药物的耐受性。本综述将聚焦于了解真菌多药耐药性途径的最新进展，包括那些与医学最相关的途径。对酿酒酵母多药耐药性的分析提供了真核微生物中多药耐药性最详细的概述。酿酒酵母的多药耐药分离株通常是由一对相关转录因子的活性变化导致的，进而引发几个靶基因的过度表达。其中最主要的是编码ATP结合盒（ABC）的基因PDR5。有趣的是，在医学上重要的念珠菌属中，获得多药耐药性涉及非常相似的途径。在白色念珠菌和光滑念珠菌中，转录激活蛋白活性的变化都会引发一种与酿酒酵母Pdr5密切相关的蛋白质Cdr1的过度表达。主要的丝状真菌病原体烟曲霉，以前被认为是通过唑类药物靶标编码基因cyp51A的改变来获得对唑类化合物（主要的抗真菌药物类别）的耐药性。最近的数据表明，除了cyp51A基因的变化外，其他途径也是烟曲霉对唑类耐药性的重要决定因素。我们将讨论一些研究结果，这些结果表明烟曲霉和念珠菌属的唑类耐药性可能比以前认为的有更多的机制相似性。
