Biology subjects

Ross, Z. K.

Publications and source records attributed to Ross, Z. K..

3 recordsLinked to original sources

bioRxiv2025

In vitro evolution of caspofungin resistance in Candidozyma auris via FKS1 hotspot I mutations results in moderate fitness trade-offs but no reduction in virulence

Resistance to echinocandins in the recently emerged pathogen Candidozyma auris (previously known as Candida auris) poses significant clinical challenges. This study reports the in vitro evolution of a caspofungin-sensitive C. auris clade II isolate to acquire caspofungin resistance. We sequenced the whole genome of the parental strain and its drug-resistant progeny. The resistant isolates harboured mutations in the FKS1 gene altering a conserved residue (S639) also mutated in caspofungin-resistant clinical isolates; demonstrating that FKS1-S639 mutations are sufficient to confer resistance to caspofungin. Using these resistant strains, we examined cross-resistance & collateral sensitivity to other antifungal drugs and to cell wall stress, cell wall ultrastructure, biofilm formation, and virulence. As expected, both FKS1-S639P and FKS1-S639Y variants exhibited resistance not only to caspofungin but also to other echinocandins. Interestingly, these resistant strains showed moderate collateral sensitivity to certain azole antifungals and increased susceptibility to cell wall stress. While cell wall chitin content was slightly elevated in resistant isolates compared to sensitive ones, overall cell wall structure and phosphomannan levels remained unchanged. Biofilm formation capabilities were similar across all strains, and virulence in invertebrate models was unaffected by the FKS1 mutations. These findings indicate that while the evolution of caspofungin resistance through FKS1 mutations does incur fitness trade-offs, it does not substantially compromise the pathogenic potential of C. auris. This underscores the complexities of evolution of antifungal resistance mechanisms in this pathogen and the impact on its biology.

microbiology↗

bioRxiv2019

Pseudohyphal growth of the emerging pathogen Candida auris is triggered by genotoxic stress through the S phase checkpoint

The morphogenetic switching between yeast cells and filaments (true hyphae and pseudohyphae) is a key cellular feature required for full virulence in many polymorphic fungal pathogens, such as Candida albicans. In the recently emerged yeast pathogen Candida auris, occasional elongation of cells has been reported. However, environmental conditions and genetic triggers for filament formation have remained elusive. Here, we report that induction of DNA damage and perturbation of replication forks by treatment with genotoxins, such as hydroxyurea, methyl methanesulfonate, and the clinically relevant fungistatic 5-fluorocytosine, causes filamentation in C. auris. The filaments formed were characteristic of pseudohyphae and not parallel-sided true hyphae. Pseudohyphal growth is apparently signalled through the S phase checkpoint and, interestingly, is Tup1-independent in C. auris. Intriguingly, the morphogenetic switching capability is strain-specific in C. auris, highlighting the heterogenous nature of the species as a whole.\n\nIMPORTANCECandida auris is a newly emerged fungal pathogen of humans. This species was first reported in 2009, when it was identified in an ear infection of a patient in Japan. However, despite intense interest in this organism as an often multidrug-resistant fungus there is little knowledge about its cellular biology. During infection of human patients, fungi are able to change cell shape from ellipsoidal yeast cells to elongated filaments to adapt to various conditions within the host organism. There are different types of filaments, which are triggered by reactions to different cues. Candida auris fails to form filaments when exposed to triggers that stimulate yeast-filament morphogenesis in other fungi. Here, we show that it does form filaments when its DNA is damaged. These conditions might arise when Candida auris cells interact with host immune cells, or growing in certain host tissues (kidney, bladder), or during treatment with antifungal drugs.

microbiology↗

bioRxiv2019

Rapid and extensive karyotype diversification in haploid clinical Candida auris isolates

Candida auris is a newly emerging pathogenic microbe, having been identified as a medically relevant fungus as recently as 2009. It is the most drug-resistant yeast species known to date and its emergence and population structure are unusual. Because of its recent emergence we are largely ignorant about fundamental aspects of its general biology, life cycle, and population dynamics. Here we report the karyotype variability of 26 C. auris strains representing the four main clades. We demonstrate that all strains are haploid and have a highly plastic karyotype containing five to seven chromosomes, which can undergo marked alterations within a short time-frame when the fungus is put under genotoxic, heat, or osmotic stress. No simple correlation was found between karyotype pattern, drug resistance, and clade affiliation indicating that karyotype heterogeneity is rapidly evolving. As with other Candida species, these marked karyotype differences between isolates are likely to have an important impact on pathogenic traits of C. auris.

microbiology↗