Kim Jong H, Cheng Luisa W, Chan Kathleen L, Tam Christina C, Mahoney Noreen, Friedman Mendel, Shilman Mikhail Martchenko, Land Kirkwood M
Foodborne Toxin Detection and Prevention Research Unit, Western Regional Research Center, Agricultural Research Service, United States Department of Agriculture, Albany, CA 94710, USA.
Healthy Processed Foods Research Unit, Western Regional Research Center, Agricultural Research Service, United States Department of Agriculture, Albany, CA 94710, USA.
Antibiotics (Basel). 2020 Nov 15;9(11):812. doi: 10.3390/antibiotics9110812.
Control of fungal pathogens is increasingly problematic due to the limited number of effective drugs available for antifungal therapy. Conventional antifungal drugs could also trigger human cytotoxicity associated with the kidneys and liver, including the generation of reactive oxygen species. Moreover, increased incidences of fungal resistance to the classes of azoles, such as fluconazole, itraconazole, voriconazole, or posaconazole, or echinocandins, including caspofungin, anidulafungin, or micafungin, have been documented. Of note, certain azole fungicides such as propiconazole or tebuconazole that are applied to agricultural fields have the same mechanism of antifungal action as clinical azole drugs. Such long-term application of azole fungicides to crop fields provides environmental selection pressure for the emergence of pan-azole-resistant fungal strains such as having TR34/L98H mutations, specifically, a 34 bp insertion into the cytochrome P450 51A () gene promoter region and a leucine-to-histidine substitution at codon 98 of . Altogether, the emerging resistance of pathogens to currently available antifungal drugs and insufficiency in the discovery of new therapeutics engender the urgent need for the development of new antifungals and/or alternative therapies for effective control of fungal pathogens. We discuss the current needs for the discovery of new clinical antifungal drugs and the recent drug repurposing endeavors as alternative methods for fungal pathogen control.
由于可用于抗真菌治疗的有效药物数量有限，控制真菌病原体的问题日益突出。传统抗真菌药物还可能引发与肾脏和肝脏相关的人体细胞毒性，包括活性氧的产生。此外，已记录到真菌对唑类药物（如氟康唑、伊曲康唑、伏立康唑或泊沙康唑）或棘白菌素类药物（包括卡泊芬净、阿尼芬净或米卡芬净）的耐药性发生率增加。值得注意的是，某些应用于农业领域的唑类杀菌剂（如丙环唑或戊唑醇）与临床唑类药物具有相同的抗真菌作用机制。在作物田长期使用此类唑类杀菌剂为泛唑耐药真菌菌株（如具有TR34/L98H突变的菌株）的出现提供了环境选择压力，具体而言，在细胞色素P450 51A（）基因启动子区域插入34个碱基对，并在的第98位密码子处发生亮氨酸到组氨酸的替换。总之，病原体对现有抗真菌药物的耐药性不断出现，以及新疗法发现的不足，迫切需要开发新的抗真菌药物和/或替代疗法，以有效控制真菌病原体。我们讨论了发现新的临床抗真菌药物的当前需求，以及最近作为控制真菌病原体的替代方法的药物重新利用努力。
