Balkis Maher M, Leidich Steven D, Mukherjee Pranab K, Ghannoum Mahmoud A
Department of Dermatology, Center for Medical Mycology, University Hospitals Research Institute of Cleveland, 11100 Euclid Avenue, Cleveland, OH 44106-5028, USA.
Drugs. 2002;62(7):1025-40. doi: 10.2165/00003495-200262070-00004.
The increased use of antifungal agents in recent years has resulted in the development of resistance to these drugs. The significant clinical implication of resistance has led to heightened interest in the study of antifungal resistance from different angles. In this article we discuss antifungal susceptibility testing, the mode of action of antifungals and mechanisms of resistance. Antifungals are grouped into five groups on the basis of their site of action: azoles, which inhibit the synthesis of ergosterol (the main fungal sterol); polyenes, which bind to fungal membrane sterol, resulting in the formation of aqueous pores through which essential cytoplasmic materials leak out; allylamines, which block ergosterol biosynthesis, leading to accumulation of squalene (which is toxic to the cells); candins (inhibitors of the fungal cell wall), which function by inhibiting the synthesis of beta 1,3-glucan (the major structural polymer of the cell wall); and flucytosine, which inhibits macromolecular synthesis. Different mechanisms contribute to the resistance of antifungal agents. These mechanisms include modification of ERG11 gene at the molecular level (gene mutation, conversion and overexpression), over expression of specific drug efflux pumps, alteration in sterol biosynthesis, and reduction in the intracellular concentration of target enzymes. Approaches to prevent and control the emergence of antifungal resistance include prudent use of antifungals, treatment with the appropriate antifungal and conducting surveillance studies to determine the frequency of resistance.
近年来抗真菌药物使用的增加导致了对这些药物耐药性的产生。耐药性的重大临床意义引发了从不同角度对抗真菌耐药性研究的浓厚兴趣。在本文中，我们讨论抗真菌药敏试验、抗真菌药物的作用方式及耐药机制。抗真菌药物根据其作用部位分为五类：唑类，抑制麦角甾醇（主要的真菌甾醇）的合成；多烯类，与真菌膜甾醇结合，导致形成水孔，重要的细胞质物质通过这些水孔泄漏出去；烯丙胺类，阻断麦角甾醇生物合成，导致角鲨烯（对细胞有毒性）积累；棘白菌素类（真菌细胞壁抑制剂），通过抑制β-1,3-葡聚糖（细胞壁的主要结构聚合物）的合成发挥作用；以及氟胞嘧啶，抑制大分子合成。不同机制导致了抗真菌药物耐药性的产生。这些机制包括在分子水平上对ERG11基因的修饰（基因突变、转化和过表达）、特定药物外排泵的过表达、甾醇生物合成的改变以及靶酶细胞内浓度的降低。预防和控制抗真菌耐药性出现的方法包括谨慎使用抗真菌药物、使用合适的抗真菌药物进行治疗以及开展监测研究以确定耐药频率。
