Biology subjects

Martinez i Zurita, A.

Publications and source records attributed to Martinez i Zurita, A..

2 recordsLinked to original sources

bioRxiv2025

Ergosterol-depleted clinical isolates of Nakaseomyces glabratus can develop multi-drug resistance without apparent fitness and virulence defects

ObjectivesNakaseomyces glabratus (formerly Candida glabrata) is a leading cause of invasive candidiasis and rapidly develops antifungal drug resistance during treatment. An increasing number of clinical isolates shows reduced susceptibility to echinocandins and azoles, leaving amphotericin B (AMB) as a last therapeutic option. Resistance of N. glabratus to this drug is rare and its underlying mechanisms are still not fully understood. Here, we describe two independent multidrug resistant (MDR) bloodstream isolates displaying resistance to AMB and anidulafungin (ANF) as well as a reduced susceptibility to azoles. MethodsWhole-genome sequencing and sterol profiling were performed on nine clinical N. glabratus isolates which were resistant to ANF and displayed resistance or low susceptibility to fluconazole (FLU) and AMB. The transcriptional response of reference strain CBS138 and an AMBR+ANFR isolate was analyzed by RNA-seq. Furthermore, PDR1 was deleted in the latter isolate to examine its influence on efflux pump gene expression. Additionally, fitness and virulence of the AMBR+ANFR isolate were examined in growth assays and a Galleria mellonella infection model. ResultsLoss of function mutations in the genes ERG3 and ERG4 is linked to ergosterol depletion and AMB resistance. Ergosterol depletion also contributed to a Pdr1-mediated up-regulation of ERG and ABC transporter genes which was associated with low FLU susceptibility. The AMBR isolates displayed no fitness defects and one of them was fully virulent in a G. mellonella infection model. ConclusionsThese findings demonstrate that ergosterol depletion in N. glabratus leads to AMB resistance without affecting fitness or virulence.

microbiology↗

bioRxiv2024

The impact of non-neutral synonymous mutations when inferring selection on non-synonymous mutations

The distribution of fitness effects (DFE) describes the proportions of new mutations that have different effects on reproductive fitness. Accurate measurements of the DFE are important because the DFE is a fundamental parameter in evolutionary genetics and has implications for our understanding of other phenomena like complex disease or inbreeding depression. Current computational methods to infer the DFE for nonsynonymous mutations from natural variation first estimate demographic parameters from synonymous variants to control for the effects of demography and background selection. Then, conditional on these parameters, the DFE is then inferred for nonsynonymous mutations. This approach relies on the assumption that synonymous variants are neutrally evolving. However, some evidence points toward synonymous mutations having measurable effects on fitness. To test whether selection on synonymous mutations affects inference of the DFE of nonsynonymous mutations, we simulated several possible models of selection on synonymous mutations using SLiM and attempted to recover the DFE of nonsynonymous mutations using Fit{partial}a{partial}i, a common method for DFE inference. Our results show that the presence of selection on synonymous variants leads to incorrect inferences of recent population growth. Furthermore, under certain parameter combinations, inferences of the DFE can have an inflated proportion of highly deleterious nonsynonymous mutations. However, this bias can be eliminated if the correct demographic parameters are used for DFE inference instead of the biased ones inferred from synonymous variants. Our work demonstrates how unmodeled selection on synonymous mutations may affect downstream inferences of the DFE.

evolutionary biology↗