Abstract
<jats:title>ABSTRACT</jats:title> <jats:sec> <jats:title/> <jats:p> Host stresses are often considered a major barrier against the emergence of echinocandin resistance (ECR) in prominent infecting organisms like <jats:italic toggle="yes">Candida albicans</jats:italic> due to fitness defects. Yet, ECR strains of <jats:italic toggle="yes">C. glabrata</jats:italic> carrying diverse amino acid changes in Fks1 and Fks2 are increasingly reported as breakthrough infections. Nonetheless, the impact of equivalent mutations in different <jats:italic toggle="yes">FKS</jats:italic> alleles on fitness has not been systematically studied. Herein, we employed a diverse array of <jats:italic toggle="yes">ex vivo</jats:italic> and <jats:italic toggle="yes">in vivo</jats:italic> models to address these questions among clinically relevant ECR mutants. All ECR mutants retained fitness during interaction with THP1 macrophages and neutrophils. Whereas a strain with a Fks2 <jats:sup>F659del</jats:sup> or <jats:italic toggle="yes">fks2Δ</jats:italic> showed fitness defects during interaction with macrophages and neutrophils. Fks2 <jats:sup>F659del</jats:sup> showed a unique susceptibility to numerous stresses, especially the combination of alternative carbon sources, low pH, and H <jats:sub>2</jats:sub> O <jats:sub>2</jats:sub> . Consistent with failure in mounting adaptive oxidative stress response during exposure to H <jats:sub>2</jats:sub> O <jats:sub>2</jats:sub> , transcriptomic analysis of intracellular Fks2 <jats:sup>F659del</jats:sup> highlighted the dysregulation of oxidative stress response genes, whereas intracellular <jats:italic toggle="yes">fks2Δ</jats:italic> showed hallmarks of metabolic dysregulation. Intriguingly, the Fks2 <jats:sup>F659del</jats:sup> mutant was outcompeted by wild type and Fks2 <jats:sup>F659V</jats:sup> in <jats:italic toggle="yes">in vivo</jats:italic> gut colonization and systemic infection models. Importantly, whereas both <jats:italic toggle="yes">FKS1</jats:italic> and <jats:italic toggle="yes">FKS2</jats:italic> were required to establish gut colonization, only <jats:italic toggle="yes">FKS2</jats:italic> was required for systemic infection. Therefore, our study supports the notion that the prevalence of ECR mutants among <jats:italic toggle="yes">C. glabrata</jats:italic> strains is likely driven by its ability to retain fitness across diverse niches. Furthermore, we identified that the essentiality of <jats:italic toggle="yes">FKS1</jats:italic> and <jats:italic toggle="yes">FKS2</jats:italic> is similarly dictated by niche-specific requirements. </jats:p> </jats:sec>