Toepfer Stephanie, Lackner Michaela, Keniya Mikhail V, Zenz Lisa-Maria, Friemert Marianne, Bracher Franz, Monk Brian C
Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin 9016, New Zealand.
Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
J Fungi (Basel). 2023 Jun 13;9(6):663. doi: 10.3390/jof9060663.
Concern about the global emergence of multidrug-resistant fungal pathogens led us to explore the use of combination therapy to combat azole resistance in . Clorgyline had previously been shown to be a multi-target inhibitor of Cdr1 and Mdr1 efflux pumps of and . A screen for antifungal sensitizers among synthetic analogs of Clorgyline detected interactions with the efflux pump azole substrates Posaconazole and Voriconazole. Of six Clorgyline analogs, M19 and M25 were identified as potential sensitizers of azole resistance. M19 and M25 were found to act synergistically with azoles against resistant clade I isolates and recombinant strains overexpressing efflux pumps. Nile Red assays with the recombinant strains showed M19 and M25 inhibited the activity of Cdr1 and Mdr1 efflux pumps that are known to play key roles in azole resistance in clades I, III, and IV. While Clorgyline, M19 and M25 uncoupled the Oligomycin-sensitive ATPase activity of Cdr1 from and , their mode of action is yet to be fully elucidated. The experimental combinations described herein provides a starting point to combat azole resistance dominated by overexpression of CauCdr1 in clades I and IV and CauMdr1 in clade III.
对全球出现的多重耐药真菌病原体的担忧促使我们探索联合治疗以对抗唑类耐药性。此前已证明氯吉兰是白色念珠菌和热带念珠菌Cdr1和Mdr1外排泵的多靶点抑制剂。在氯吉兰的合成类似物中筛选抗真菌增敏剂时，发现其与白色念珠菌外排泵唑类底物泊沙康唑和伏立康唑存在相互作用。在六种氯吉兰类似物中，M19和M25被鉴定为唑类耐药的潜在增敏剂。发现M19和M25与唑类药物协同作用，对抗I类耐药白色念珠菌分离株和过表达外排泵的重组白色念珠菌菌株。对重组菌株进行尼罗红测定表明，M19和M25抑制了Cdr1和Mdr1外排泵的活性，已知这些外排泵在I、III和IV类白色念珠菌的唑类耐药中起关键作用。虽然氯吉兰、M19和M25使Cdr1的寡霉素敏感ATP酶活性与白色念珠菌和热带念珠菌解偶联，但其作用方式尚未完全阐明。本文所述的实验组合为对抗I类和IV类白色念珠菌中CauCdr1过表达以及III类白色念珠菌中CauMdr1过表达主导的唑类耐药提供了一个起点。
