Mazumdar, R. | bioRxiv Science

bioRxiv2026

Proteome remodelling in Candida auris during early host adaptation in-vitro and in-vivo

Candida auris is an emerging fungal pathogen posing a serious global health threat due to its high transmissibility and multidrug resistance profile. Despite recent molecular advances in scrutinizing this enigmatic microbe, much of our understanding in regards to its pathomechanisms still remain unelucidated. Since, microbial pathogenesis is modulated by a dynamic interplay between the host and the pathogen, dissecting such host-pathogen interaction involving C. auris can shed novel insights into its pathogenic cascade. As such, to further characterize the virulence repertoire of C. auris, this study applied an integrated quantitative proteomics strategy to scrutinize early-phase of infection. We utilized an in-vitro and an in-vivo experimental setup based on immune cells and murine model. Integrated proteomic analysis revealed a coordinated remodelling of cellular processes by C. auris during host-pathogen interaction, including downregulation of translational machinery, and modulation of molecules involved in metabolic rewiring, stress-response, and structural rearrangements. Collectively, these findings suggests that survival of C. auris under host-immune pressure is accompanied by rapid context-dependent molecular adaptations. IO_SCPLOWMPORTANCEC_SCPLOWCandida auris is a critical high priority fungal pathogen classified by the World Health Organization (WHO) that constitute a serious threat to global health. Often termed as a superbug due to its high transmissibility and multidrug resistant profile, the microbe has spread across the globe and is capable of causing high mortality rates. Molecular studies scrutinizing the pathogenic mechanisms of C. auris are limited and represents a major bottleneck to decipher and device intervention strategies against this enigmatic pathogen. As such, this study is aimed at widening the molecular knowledge spectrum of C. auris in regards to its virulence and pathogenesis. Here we dissect the host-pathogen interaction of C. auris by establishing experimental infection models and subsequently applying an integrated proteomics strategy to capture the organisms virulence repertoire modulating fungal pathogenesis.

microbiology↗

bioRxiv2026

A targeted drug-repurposing strategy identifies Tavaborole (Kerydin) as a potent fungistatic agent against Candida auris

Candidozyma auris (Candida auris) is an emerging multidrug-resistant fungal pathogen posing a major global health threat. In this study, we employed a targeted drug-repurposing strategy to identify novel indications for existing FDA-approved compounds against C. auris, leading to the identification of Tavaborole as a potent fungistatic agent. Tavaborole displayed robust activity across all five tested clades of C. auris, as well as against Candida albicans and Candida glabrata. To investigate drug resistance mechanisms of C. auris, we applied quantitative proteomics analyses following exposure to Tavaborole and Amphotericin B (AmB), complemented by electron microscopy. Proteomic profiling revealed that C. auris mounts distinct but overlapping adaptive responses to antifungal stress, involving stress response pathways, metabolic reprogramming and amino acid biosynthesis. While Tavaborole primarily induced targeted stress adaptation, AmB triggered a broader, multi-pronged resistance response including oxidative stress mitigation, osmolyte production and metabolic remodeling. Shared alterations in glycogen metabolism and amino acid biosynthesis suggest conserved antifungal adaptation mechanisms. Altogether, this study highlights Tavaborole as a promising antifungal candidate against C. auris, sheds novel insights into drug resistance mechanisms employed the pathogen and delivers a drug-repurposing procedure highly customizable to target other microorganisms. ImportanceCandida auris is an emerging multidrug-resistant fungal pathogen responsible for healthcare-associated infections representing a high-priority antimicrobial resistance (AMR) threat due to its limited treatment options, high transmissibility, and capacity to cause severe and often fatal outbreaks. The slow pace of antifungal drug development underscores the urgent need for alternative strategies to expand the antifungal arsenal against priority pathogens such as C. auris. In this study, we demonstrate that a targeted drug-repurposing approach can efficiently identify antifungal activity from a small, curated set of FDA-approved compounds, leading to the discovery of Tavaborole as a fungistatic agent with broad activity across multiple C. auris clades. By integrating a customizable drug screening procedure with quantitative proteomics and electron microscopy, this work provides insights into antifungal resistance mechanisms. This study highlights how rational drug-repurposing strategies can rapidly identify clinically relevant drug candidates to counter emerging pathogens and address antifungal resistance.

microbiology↗