Madurella mycetomatis, the main causative agent of eumycetoma, is highly susceptible to olorofim
Madurella mycetomatis, the main causative agent of eumycetoma, is highly susceptible to olorofim
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DOI：
10.1093/jac/dkz529
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发表时间：
2020-04-01
影响因子：
5.2
通讯作者：
van de Sande, Wendy
中科院分区：
文献类型：
--
作者：
Lim, Wilson;Eadie, Kimberly;van de Sande, Wendy
目的：真菌瘤目前采用伊曲康唑联合手术治疗，但疗效有限。最近，一种新的抗真菌药物orotomides的主要候选药物olorofim进入了治疗侵袭性真菌感染的II期临床试验。本研究测定了奥洛菲姆对真菌病的主要病原菌--霉菌马杜雷氏菌（Madurella mycetomatis）的活性。通过靶基因二氢乳清酸脱氢酶（DHODH）的计算机比较和体外敏感性测试来确定真菌病。我们还研究了奥洛菲姆和伊曲康唑对M.结果：M.真菌和烟曲霉在它们的DHODH DNA序列中共有7个预测结合残基中的6个，预测了对奥洛菲姆的敏感性。Olorofim对M.在体内对霉菌的MIC范围为0.004 - 0.125 mg/L，MIC 90为0.063 mg/L。Olorofim的MIC比伊曲康唑的MIC低一个稀释级。体外相互作用研究表明，Olorofim和伊曲康唑联合使用时无明显作用。mycetomatis，并应进一步评估在体内作为这种疾病的治疗选择。
Objectives: Eumycetoma is currently treated with a combination of itraconazole therapy and surgery, with Limited success. Recently, olorofim, the Lead candidate of the orotomides, a novel doss of antifungai agents, entered a Phase II trial for the treatment of invasive fungal infections. Here we determined the activity of olorofim against Madurella mycetomatis, the main causative agent of eumycetoma.Methods: Activity of olorofim against M. mycetomatis was determined by in silico comparison of the target gene, dihydroorotate dehydrogenase (DHODH), and in vitro susceptibility testing. We also investigated the in vitro interaction between olorofim and itraconazole against M. mycetomatis.Results: M. mycetomatis and Aspergillus fumigatus share six out of seven predicted binding residues in their DHODH DNA sequence, predicting susceptibility to olorofim. Olorofim demonstrated excellent potency against M. mycetomatis in vivo with MICs ranging from 0.004 to 0.125 mg/L and an MIC90 of 0.063 mg/L. Olorofim MICs were mostly one dilution step Lower than the itraconazole MICs. In vitro interaction studies demonstrated that olorofim and itraconazole work indifferently when combined.Conclusions: We demonstrated olorofim has potent in vitro activity against M. mycetomatis and should be further evaluated in vivo as a treatment option for this disease.