Multiple genome analysis of Candida glabrata clinical isolates renders new insights into genetic diversity and drug resistance determinants
Authors:Pedro Pais1,2,3,#, Mónica Galocha1,2,3,#, Azusa Takahashi-Nakaguchi4, Hiroji Chibana4 and Miguel C. Teixeira1,2,3
doi: 10.15698/mic2022.11.786
Volume 9, pp. 174 to 189, published 13/10/2022.
1 Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal.
2 iBB – Institute for Bioengineering and Biosciences, Biological Sciences Research Group, Instituto Superior Técnico, Lisboa, Portugal.
3 Associate Laboratory i4HB—Institute for Health and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa, Portugal.
4 Medical Mycology Research Center (MMRC), Chiba University, Chiba, Japan.
# These authors contributed equally to this work.
Keywords:
Candida glabrata, clinical isolates, SNP, CNV, genome variation, drug resistance
Corresponding Author(s):
Conflict of interest statement:
Please cite this article as:
Pedro Pais, Mónica Galocha, Azusa Takahashi-Nakaguchi, Hiroji Chibana and Miguel C. Teixeira (2022). Multiple genome analysis of Candida glabrata clinical isolates renders new insights into genetic diversity and drug resistance determinants. Microbial Cell 9(11): 174-189. doi: 10.15698/mic2022.11.786
© 2022 Pais et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduc-tion in any medium, provided the original author and source are acknowledged.
Abstract:
The emergence of drug resistance significantly hampers the treatment of human infections, including those caused by fungal pathogens such as Candida species. Candida glabrata ranks as the second most common cause of candidiasis worldwide, supported by rapid acquisition of resistance to azole and echinocandin antifungals frequently prompted by single nucleotide polymorphisms (SNPs) in resistance associated genes, such as PDR1 (azole resistance) or FKS1/2 (echinocandin resistance). To determine the frequency of polymorphisms and genome rearrangements as the possible genetic basis of C. glabrata drug resistance, we assessed genomic variation across 94 globally distributed isolates with distinct resistance phenotypes, whose sequence is deposited in GenBank. The genomes of three additional clinical isolates were sequenced, in this study, including two azole resistant strains that did not display Gain-Of-Function (GOF) mutations in the transcription factor encoding gene PDR1. Genomic variations in susceptible isolates were used to screen out variants arising from genome diversity and to identify variants exclusive to resistant isolates. More than half of the azole or echinocandin resistant isolates do not possess exclusive polymorphisms in PDR1 or FKS1/2, respectively, providing evidence of alternative genetic basis of antifungal resistance. We also identified copy number variations consistently affecting a subset of chromosomes. Overall, our analysis of the genomic and phenotypic variation across isolates allowed to pinpoint, in a genome-wide scale, genetic changes enriched specifically in antifungal resistant strains, which provides a first step to identify additional determinants of antifungal resistance. Specifically, regarding the newly sequenced strains, a set of mutations/genes are proposed to underlie the observed unconventional azole resistance phenotype.