Department of Medical Microbiology, Radboud University Medical Centre, Nijmegen, The Netherlands.
Center of Expertise in Mycology Radboudumc/CWZ, Nijmegen, The Netherlands.
J Antimicrob Chemother. 2017 Sep 1;72(9):2548-2552. doi: 10.1093/jac/dkx177.
F901318 is a new antifungal agent with a novel mechanism of action with activity against Aspergillus species. We investigated the in vitro activity of F901318 against a collection of Aspergillus isolates.
A total of 213 Aspergillus isolates were used in this study. A total of 143 Aspergillus fumigatus sensu stricto isolates were used, of which 133 were azole resistant [25 TR34/L98H; 25 TR46/Y121F/T289A; 33 A. fumigatus with cyp51A-associated point mutations (25 G54, 1 G432 and 7 M220); and 50 azole-resistant A. fumigatus without known resistance mechanisms]. Ten azole-susceptible A. fumigatus isolates were used as WT controls. The in vitro activity was also determined against Aspergillus calidoustus (25 isolates), Aspergillus flavus (10), Aspergillus nidulans (10) and Aspergillus tubingensis (25). F901318 activity was compared with that of itraconazole, voriconazole, posaconazole, isavuconazole, amphotericin B and anidulafungin. Minimum effective concentrations and MICs were determined using the EUCAST broth microdilution method.
F901318 was active against all tested isolates: A. fumigatus WT, MIC90 0.125 mg/L (range 0.031-0.125); TR34/L98H,TR46/Y121F/T289A and azole resistant without known resistance mechanisms, MIC90 0.125 mg/L (range 0.031-0.25); A. fumigatus with cyp51A-associated point mutations, MIC90 0.062 mg/L (range 0.015-0.125); and other species, A. calidoustus MIC90 0.5 mg/L (range 0.125-0.5), A. flavus MIC90 0.062 mg/L (range 0.015-0.62), A. nidulans MIC90 0.125 mg/L (range 0.062-0.25) and A. tubingensis MIC90 0.062 mg/L (range 0.015-0.25).
F901318 showed potent and consistent in vitro activity against difficult-to-treat Aspergillus spp. with intrinsic and acquired antifungal resistance due to known and unknown resistance mechanisms, suggesting no significant implications of azole resistance mechanisms for the mode of action of F901318.
F901318 是一种具有新型作用机制的新型抗真菌药物，对曲霉菌属具有活性。我们研究了 F901318 对曲霉菌分离株的体外活性。
本研究共使用了 213 株曲霉菌分离株。共使用了 143 株烟曲霉严格意义上的分离株，其中 25 株 TR34/L98H；25 株 TR46/Y121F/T289A；33 株与 cyp51A 相关点突变的烟曲霉（25 株 G54、1 株 G432 和 7 株 M220）；50 株具有未知耐药机制的唑类耐药烟曲霉。10 株唑类敏感烟曲霉作为 WT 对照。还测定了对蛹虫草（25 株）、黄曲霉（10 株）、构巢曲霉（10 株）和管碟曲霉（25 株）的体外活性。将 F901318 的活性与伊曲康唑、伏立康唑、泊沙康唑、伊曲康唑、两性霉素 B 和安尼芬净进行了比较。使用 EUCAST 肉汤微量稀释法测定最小有效浓度和 MIC。
F901318 对所有测试分离株均有活性：烟曲霉 WT，MIC90 0.125μg/L（范围 0.031-0.125）；TR34/L98H、TR46/Y121F/T289A 和具有未知耐药机制的唑类耐药菌，MIC90 0.125μg/L（范围 0.031-0.25）；与 cyp51A 相关的点突变烟曲霉，MIC90 0.062μg/L（范围 0.015-0.125）；和其他种，蛹虫草 MIC90 0.5μg/L（范围 0.125-0.5）、黄曲霉 MIC90 0.062μg/L（范围 0.015-0.62）、构巢曲霉 MIC90 0.125μg/L（范围 0.062-0.25）和管碟曲霉 MIC90 0.062μg/L（范围 0.015-0.25）。
F901318 对具有内在和获得性抗真菌耐药性的难治性曲霉菌属具有强大且一致的体外活性，这表明唑类耐药机制对 F901318 的作用模式没有重大影响。
