Borgeat Valentin, Brandalise Danielle, Grenouillet Frédéric, Sanglard Dominique
Institute of Microbiology, University of Lausanne and University Hospital, CH-1011 Lausanne, Switzerland.
Pole de Biologie Médicale, Centre Hospitalier Universitaire (CHU) Besançon, F-25000 Besançon, France.
J Fungi (Basel). 2021 Sep 15;7(9):760. doi: 10.3390/jof7090760.
is an opportunistic pathogen in humans that causes infrequent but difficult-to-treat diseases. Antifungal drugs are used in the clinic to treat infections, however, this fungus can rapidly acquire antifungal resistance to all known antifungal drugs (multidrug resistance). acquires azole resistance by gain-of-function (GOF) mutations in the transcriptional regulator . controls the expression of a major facilitator transporter () that is important for fluconazole resistance. Here, we addressed the role of the ATP Binding Cassette (ABC) transporter as additional mediator of azole resistance in expression in isolates with GOF mutations was higher compared to wild types, which suggests that is an additional (direct or indirect) target of . deletion in the azole-resistant isolate P3 (V688G GOF) revealed that MICs of long-tailed azoles, itraconazole and posaconazole, were decreased compared to P3, which is consistent with the role of this ABC transporter in the efflux of these azoles. Fluconazole MIC was only decreased when was deleted in the background of an Δ mutant from P3, which underpins the dominant role of in the resistance of the short-tailed azole fluconazole. With R6G efflux readout as Cdr1 efflux capacity, our data showed that R6G efflux was increased in P3 compared to an azole-susceptible wild type parent, and diminished to background levels in mutant strains lacking . Milbemycin oxim A3, a known inhibitor of fungal ABC transporters, mimicked efflux phenotypes of Δ mutants. We therefore provided evidence that is an additional mediator of azole resistance in and that regulation is dependent on and associated GOF mutations.
是人类中的一种机会致病菌，可引起罕见但难以治疗的疾病。临床上使用抗真菌药物来治疗感染，然而，这种真菌可迅速获得对所有已知抗真菌药物的抗药性（多重耐药性）。通过转录调节因子中的功能获得性（GOF）突变获得唑类抗性。控制对氟康唑抗性很重要的主要易化转运蛋白（）的表达。在这里，我们探讨了ATP结合盒（ABC）转运蛋白作为唑类抗性的额外介质在中的作用。与野生型相比，具有GOF突变的分离株中表达更高，这表明是（直接或间接）的额外靶点。唑类抗性分离株P3（V688G GOF）中的缺失表明，与P3相比，长尾唑类、伊曲康唑和泊沙康唑的最低抑菌浓度（MIC）降低，这与该ABC转运蛋白在这些唑类外排中的作用一致。仅在来自P3的Δ突变体背景中缺失时，氟康唑MIC才降低，这突出了在短尾唑类氟康唑抗性中的主导作用。以R6G外排读数作为Cdr1外排能力，我们的数据表明，与唑类敏感的野生型亲本相比，P3中的R6G外排增加，而在缺乏的突变菌株中降低至背景水平。米尔倍霉素肟A3是一种已知的真菌ABC转运蛋白抑制剂，模拟了Δ突变体的外排表型。因此，我们提供了证据表明是唑类抗性的额外介质，并且调节依赖于和相关的GOF突变。
