Resistance profiling of Aspergillus fumigatus to olorofim indicates absence of intrinsic resistance and unveils the molecular mechanisms of acquired olorofim resistance.
Resistance profiling of Aspergillus fumigatus to olorofim indicates absence of intrinsic resistance and unveils the molecular mechanisms of acquired olorofim resistance.
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DOI：
10.1080/22221751.2022.2034485
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发表时间：
2022-12
影响因子：
13.2
通讯作者：
Verweij PE
中科院分区：
文献类型：
--
作者：
Buil JB;Oliver JD;Law D;Baltussen T;Zoll J;Hokken MWJ;Tehupeiory-Kooreman M;Melchers WJG;Birch M;Verweij PE
Olorofim（F901318）是一种目前正在临床开发的新型抗真菌剂，对包括烟曲霉在内的许多丝状真菌显示出体外和体内活性。在本研究中，我们筛选了A.烟曲霉菌株对内源性奥洛菲姆耐药。并对A.烟曲霉以获得奥洛菲姆抗性表型。975例临床标本中未发现固有耐药。烟曲霉菌株然而，我们发现，在实验室条件下，使用大量分生孢子和olorofim暴露可以选择具有增加的olorofim MIC（> 8 mg/L）的分离物。 评估A.烟曲霉的浓度高于伏立康唑，但低于伊曲康唑。对具有>8 mg/L的奥洛菲姆MIC的同基因分离物的PyrE基因进行测序，鉴定了在基因座G119处具有热点的各种氨基酸取代。 Olorofim显示对突变的靶蛋白二氢乳清酸脱氢酶（DHODH）具有降低的亲和力，并且通过将突变直接引入A.烟熏。然后，我们研究了G119突变是否与A.烟熏。这些实验显示，具有G119 V置换的菌株的生长速率有小但显著的降低，而具有G119 C置换的菌株没有表现出生长速率的降低。这些体外发现在体内致病性模型中得到证实。
Olorofim (F901318) is a new antifungal currently under clinical development that shows both in vitro and in vivo activity against a number of filamentous fungi including Aspergillus fumigatus. In this study, we screened A. fumigatus isolates for intrinsic olorofim-resistant A. fumigatus and evaluated the ability of A. fumigatus to acquire an olorofim-resistant phenotype. No intrinsic resistance was found in 975 clinical A. fumigatus isolates. However, we found that isolates with increased olorofim MICs (> 8 mg/L) could be selected using a high number of conidia and olorofim exposure under laboratory conditions. Assessment of the frequency of acquired olorofim resistance development of A. fumigatus was shown to be higher than for voriconazole but lower than for itraconazole. Sequencing the PyrE gene of isogenic isolates with olorofim MICs of >8 mg/L identified various amino acid substitutions with a hotspot at locus G119. Olorofim was shown to have reduced affinity to mutated target protein dihydroorotate dehydrogenase (DHODH) and the effect of these mutations was proven by introducing the mutations directly in A. fumigatus. We then investigated whether G119 mutations were associated with a fitness cost in A. fumigatus. These experiments showed a small but significant reduction in growth rate for strains with a G119V substitution, while strains with a G119C substitution did not exhibit a reduction in growth rate. These in vitro findings were confirmed in an in vivo pathogenicity model.
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影响因子：
4.9
作者：
Jorgensen, Karin Meinike;Astvad, Karen M T;Arendrup, Maiken Cavling
通讯作者：
Arendrup, Maiken Cavling
影响因子：
2.9
作者：
Bertuzzi M;van Rhijn N;Krappmann S;Bowyer P;Bromley MJ;Bignell EM
通讯作者：
Bignell EM
DOI：
10.1016/j.fgb.2018.02.003
发表时间：
2018-04
期刊：
Fungal genetics and biology : FG & B
影响因子：
--
作者：
Ballard E;Melchers WJG;Zoll J;Brown AJP;Verweij PE;Warris A
通讯作者：
Warris A
影响因子：
5.2
作者：
Kirchhoff, Lisa;Dittmer, Silke;Steinmann, Joerg
通讯作者：
Steinmann, Joerg
影响因子：
5.2
作者：
Buil, Jochem B.;Bruggemann, Roger J. M.;Verweij, Paul E.
通讯作者：
Verweij, Paul E.