Rasouli Koohi Samira, Shankarnarayan Shamanth A, Galon Clare Maristela, Charlebois Daniel A
Department of Physics, University of Alberta, Edmonton, AB T6G 2R3, Canada.
Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada.
Biomedicines. 2023 Mar 14;11(3):898. doi: 10.3390/biomedicines11030898.
Antimicrobial resistance is a global health crisis to which pathogenic fungi make a substantial contribution. The human fungal pathogen is of particular concern due to its rapid spread across the world and its evolution of multidrug resistance. Fluconazole failure in has been recently attributed to antifungal "tolerance". Tolerance is a phenomenon whereby a slow-growing subpopulation of tolerant cells, which are genetically identical to susceptible cells, emerges during drug treatment. We use microbroth dilution and disk diffusion assays, together with image analysis, to investigate antifungal tolerance in to all three classes of antifungal drugs used to treat invasive candidiasis. We find that (1) is tolerant to several common fungistatic and fungicidal drugs, which in some cases can be detected after 24 h, as well as after 48 h, of antifungal drug exposure; (2) the tolerant phenotype reverts to the susceptible phenotype in ; and (3) combining azole, polyene, and echinocandin antifungal drugs with the adjuvant chloroquine in some cases reduces or eliminates tolerance and resistance in patient-derived isolates. These results suggest that tolerance contributes to treatment failure in infections for a broad range of antifungal drugs, and that antifungal adjuvants may improve treatment outcomes for patients infected with antifungal-tolerant or antifungal-resistant fungal pathogens.
抗菌药物耐药性是一场全球健康危机，致病真菌在其中起到了很大作用。人类真菌病原体因其在全球的迅速传播以及多药耐药性的演变而备受关注。最近，白色念珠菌对氟康唑治疗失败被归因于抗真菌“耐受性”。耐受性是一种现象，即在药物治疗期间会出现一群生长缓慢的耐受细胞亚群，这些细胞与敏感细胞在基因上是相同的。我们使用微量肉汤稀释法和纸片扩散法，并结合图像分析，来研究白色念珠菌对用于治疗侵袭性念珠菌病的所有三类抗真菌药物的抗真菌耐受性。我们发现：（1）白色念珠菌对几种常见的抑菌和杀菌药物具有耐受性，在某些情况下，在接触抗真菌药物24小时以及48小时后都能检测到这种耐受性；（2）在白色念珠菌中，耐受表型会恢复为敏感表型；（3）在某些情况下，将唑类、多烯类和棘白菌素类抗真菌药物与佐剂氯喹联合使用可降低或消除患者来源的白色念珠菌分离株中的耐受性和耐药性。这些结果表明，耐受性导致了白色念珠菌感染对多种抗真菌药物治疗失败，并且抗真菌佐剂可能会改善感染了抗真菌耐受或抗真菌耐药真菌病原体患者的治疗结果。
