SLA1 governs azole resistance in Candidozyma auris via mitochondrial ROS-driven efflux pump expression

Candidozyma auris is an emerging multidrug-resistant fungal pathogen, and widespread fluconazole (FLC) resistance severely limits clinical treatment options. Overexpression of the efflux transporter CDR1 represents a major driver of azole resistance; however, how oxidative stress modulates this process remains poorly understood. This study aimed to identify novel regulators that connect oxidative stress adaptation with azole resistance in C. auris.

We constructed SLA1 deletion mutants of C. auris. SLA1 encodes a conserved regulator of cytoskeletal organization and membrane trafficking. We evaluated mitochondrial homeostasis, mtROS accumulation, and CDR1 expression. Pharmacological mitochondrial perturbation was used to disentangle the individual effects of ROS accumulation and mitochondrial dysfunction on FLC resistance. We further assessed cell envelope integrity, in vivo virulence, and the transcriptional correlation between SLA1 and CDR1 using clinical isolates.

SLA1 deletion triggered mitochondrial dysfunction, increased mtROS accumulation, upregulated CDR1, and enhanced azole resistance. Pharmacological disruption of mitochondria further raised ROS levels yet suppressed CDR1, depleted ATP, accumulated NADH, and abolished FLC resistance. This indicates that ROS elevation alone cannot sustain resistance under severe mitochondrial impairment. SLA1 knockout compromised cell envelope integrity and attenuated in vivo virulence, revealing a fitness trade-off during antifungal adaptation. Clinical isolates exhibited a significant inverse correlation between SLA1 and CDR1 transcript levels.

This study identifies SLA1 as a previously uncharacterized modulator of oxidative stress adaptation and azole susceptibility in C. auris. Mitochondrial functional status governs the relationship between oxidative stress and azole resistance. The SLA1-dependent axis promotes antifungal resistance at the expense of reduced virulence. These findings reveal a new mechanism of drug adaptation in C. auris and point to a potential target for combating multidrug-resistant C. auris.