Garcia-Rubio Rocio, Hernandez Rosa Y, Clear Alissa, Healey Kelley R, Shor Erika, Perlin David S
Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, United States.
Department of Biology, William Paterson University, Wayne, NJ, United States.
Front Microbiol. 2021 Jun 30;12:702779. doi: 10.3389/fmicb.2021.702779. eCollection 2021.
Fungal infections are on the rise, and emergence of drug-resistant strains refractory to treatment is particularly alarming. Resistance to azole class antifungals, which have been extensively used worldwide for several decades, is so high in several prevalent fungal pathogens, that another drug class, the echinocandins, is now recommended as a first line antifungal treatment. However, resistance to echinocandins is also prominent, particularly in certain species, such as . The echinocandins target 1,3-β-glucan synthase (GS), the enzyme responsible for producing 1,3-β-glucans, a major component of the fungal cell wall. Although echinocandins are considered fungicidal, exhibits echinocandin tolerance both and , where a subset of the cells survives and facilitates the emergence of echinocandin-resistant mutants, which are responsible for clinical failure. Despite this critical role of echinocandin tolerance, its mechanisms are still not well understood. Additionally, most studies of tolerance are conducted and are thus not able to recapitulate the fungal-host interaction. In this study, we focused on the role of cell wall integrity factors in echinocandin tolerance in We identified three genes involved in the maintenance of cell wall integrity - , , and - that promote echinocandin tolerance both and in a mouse model of gastrointestinal (GI) colonization. In particular, we show that mice colonized with strains carrying deletions of these genes were more effectively sterilized by daily caspofungin treatment relative to mice colonized with the wild-type parental strain. Furthermore, consistent with a role of tolerant cells serving as a reservoir for generating resistant mutations, a reduction in tolerance was associated with a reduction in the emergence of resistant strains. Finally, reduced susceptibility in these strains was due both to the well described -dependent mechanisms and as yet unknown, -independent mechanisms. Together, these results shed light on the importance of cell wall integrity maintenance in echinocandin tolerance and emergence of resistance and lay the foundation for future studies of the factors described herein.
真菌感染正在增加，耐药菌株的出现对治疗产生抗性尤其令人担忧。在全球范围内广泛使用了几十年的唑类抗真菌药物，在几种常见真菌病原体中的耐药性非常高，以至于现在推荐另一类药物棘白菌素作为一线抗真菌治疗药物。然而，对棘白菌素的耐药性也很突出，特别是在某些物种中，如 。棘白菌素靶向1,3-β-葡聚糖合酶（GS），该酶负责产生1,3-β-葡聚糖，这是真菌细胞壁的主要成分。尽管棘白菌素被认为具有杀菌作用，但 在 和 中均表现出对棘白菌素的耐受性，其中一部分细胞存活下来并促进了棘白菌素耐药突变体的出现，这些突变体导致临床治疗失败。尽管棘白菌素耐受性具有这一关键作用，但其机制仍未得到很好的理解。此外，大多数耐受性研究都是在 进行的，因此无法概括真菌与宿主的相互作用。在本研究中，我们聚焦于细胞壁完整性因子在 中对棘白菌素耐受性的作用。我们鉴定出三个参与维持细胞壁完整性的基因 - 、 和 - 它们在 和胃肠道（GI）定植的小鼠模型中均促进了对棘白菌素的耐受性。特别是，我们表明，与定植野生型亲本菌株的小鼠相比，定植携带这些基因缺失菌株的小鼠通过每日卡泊芬净治疗能更有效地被清除真菌。此外，与耐受性细胞作为产生抗性突变的储存库的作用一致，耐受性的降低与抗性菌株出现的减少相关。最后，这些菌株中敏感性降低既归因于已充分描述的 - 依赖性机制，也归因于尚未知的 - 非依赖性机制。总之，这些结果揭示了维持细胞壁完整性在棘白菌素耐受性和抗性出现中的重要性，并为本文所述因素的未来研究奠定了基础。
