Segéňová Ivana, Víglaš Ján, Pagáč Tomáš, Olejníková Petra
Institute of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, 812 37 Bratislava, Slovakia.
J Fungi (Basel). 2025 Jun 2;11(6):428. doi: 10.3390/jof11060428.
Understanding the interplay between antifungal resistance, stress adaptation, and virulence in is critical for more effective treatment outcomes. In this study, we investigate six clinical isolates of from the hospitals of the Czech Republic, focusing on their resistance profiles, stress responses, and survival mechanisms under antifungal pressure. Notably, we have shown that azole-susceptible strains were able to form persister cells under supra-MIC concentrations, highlighting an emerging non-genetic survival mechanism. Stress response profiling demonstrated differential susceptibility to agents targeting signal transduction pathways, as principal component analysis proved that even azole-resistant strains might rely on these pathways. Combinatorial treatment with posaconazole and dithiothreitol enhanced antifungal efficacy regardless of the susceptibility of the strains. Fitness assays revealed that azole resistance imposed a competitive disadvantage in azole-free conditions. In vivo virulence assessment in larvae revealed strain-specific pathogenicity that did not directly correlate with resistance. Together, our findings illustrate the multifactorial nature of fungal survival and emphasize that stress adaptation, tolerance, and persistence significantly affect treatment efficacy and outcomes, even in the absence of classical resistance mechanisms. Targeting stress response pathways emerges as a promising strategy to enhance the efficacy of existing antifungal agents and manage resistance in .
了解抗真菌耐药性、应激适应和毒力之间的相互作用对于获得更有效的治疗结果至关重要。在本研究中，我们调查了来自捷克共和国医院的6株临床分离株，重点关注它们在抗真菌压力下的耐药谱、应激反应和生存机制。值得注意的是，我们发现对唑类敏感的菌株能够在高于最低抑菌浓度（supra-MIC）的浓度下形成持留菌，这突出了一种新出现的非遗传生存机制。应激反应谱分析表明，菌株对靶向信号转导途径的药物敏感性存在差异，因为主成分分析证明，即使是对唑类耐药的菌株也可能依赖这些途径。无论菌株的敏感性如何，泊沙康唑和二硫苏糖醇联合治疗均可提高抗真菌疗效。适应性测定表明，在无唑类的条件下，唑类耐药性会带来竞争劣势。对果蝇幼虫进行的体内毒力评估显示，菌株具有特异性致病性，且与耐药性无直接关联。总之，我们的研究结果说明了真菌生存的多因素性质，并强调即使在没有经典耐药机制的情况下，应激适应、耐受性和持留性也会显著影响治疗效果和结果。针对应激反应途径是一种有前景的策略，可提高现有抗真菌药物的疗效并应对白色念珠菌的耐药性。
