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First Genome Sequences of Two Multidrug-Resistant Candida haemulonii var. vulnera Isolates From Pediatric Patients With Candidemia.

ABSTRACT: Candida haemulonii is a complex formed by C. haemulonii sensu stricto, C. haemulonii var. vulnera, and C. duobushaemulonii. Members of this complex are opportunistic pathogens closely related to C. pseudohaemulonii, C. lusitaniae, and C. auris, all members of a multidrug-resistant clade. Complete genome sequences for all members of this group are available in the GenBank database, except for C. haemulonii var. vulnera. Here, we report the first draft genomes of two C. haemulonii var. vulnera (isolates K1 and K2) and comparative genome analysis of closely related fungal species. The isolates were biofilm producers and non-susceptible to amphotericin B and fluconazole. The draft genomes comprised 350 and 387 contigs and total genome sizes of 13.21 and 13.26 Mb, with 5,479 and 5,507 protein-coding genes, respectively, allowing the identification of virulence and resistance genes. Comparative analyses of orthologous genes within the multidrug-resistant clade showed a total of 4,015 core clusters, supporting the conservation of 24,654 proteins and 3,849 single-copy gene clusters. Candida haemulonii var. vulnera shared a larger number of clusters with C. haemulonii and C. auris; however, more singletons were identified in C. lusitaniae and C. auris. Additionally, a multiple sequence alignment of Erg11p proteins revealed variants likely involved in reduced susceptibility to azole and polyene antifungal agents. The data presented in this work will, therefore, be of utmost importance for researchers studying the biology of the C. haemulonii complex and related species.

SUBMITTER: Rodrigues LS

PROVIDER: S-EPMC7350289 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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First Genome Sequences of Two Multidrug-Resistant Candida haemulonii var. vulnera Isolates From Pediatric Patients With Candidemia.

Rodrigues Luiza Souza LS Gazara Rajesh Kumar RK Passarelli-Araujo Hemanoel H Valengo Andressa Eloisa AE Pontes Paula Veronesi Marinho PVM Nunes-da-Fonseca Rodrigo R de Souza Robson Francisco RF Venancio Thiago Motta TM Dalla-Costa Libera Maria LM

Frontiers in microbiology 20200703

Candida haemulonii is a complex formed by C. haemulonii sensu stricto, C. haemulonii var. vulnera, and C. duobushaemulonii. Members of this complex are opportunistic pathogens closely related to C. pseudohaemulonii, C. lusitaniae, and C. auris, all members of a multidrug-resistant clade. Complete genome sequences for all members of this group are available in the GenBank database, except for C. haemulonii var. vulnera. Here, w ...[more]

PMID: 32719671

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Project description:Candida haemulonii, a close relative of Candida auris, is an emerging pathogen which frequently shows multidrug resistance especially to triazoles, the most used antifungal drugs. The mechanisms of drug resistance in C. haemulonii, however, are largely unknown. Here, we sequenced and annotated the genomes of two reference strains from the C. haemulonii complex, compared the phenotypes, genomes, and transcriptomes of a triazole-susceptible and two triazole-resistant C. haemulonii strains, and identified triazole susceptibility, morphology, fitness, and the major genetic and gene expression differences between the strains. A multidrug efflux gene, CDR1, was recurrently found to be upregulated for expression in triazole-resistant strains. Blocking the activity of Cdr1 increased the susceptibility to triazoles strikingly. Comparative transcriptome analysis also demonstrated impaired cell wall integrity, filamentous growth, and iron homeostasis in triazole-resistant strains. Finally, we also identified a zinc-binding MHR family transcription regulator gene that mutated in triazole-resistant strains spontaneously, contributing to the changes of morphology and, possibly, cell wall integrity between the strains. The study provided important clues for future studies exploring the mechanisms of multidrug resistance and related phenotypic differences of C. haemulonii strains.IMPORTANCE A comprehensive, multi-omic survey was performed to disclose the genetic backgrounds and differences between multidrug-resistant and -susceptible C. haemulonii strains. Genes were identified with mutations or significant expression differences in multidrug-resistant compared to multidrug-susceptible strains, which were mainly involved in multidrug resistance, stress fitness, and morphology. The Cdr1-encoding gene, C. haemulonii2486 (CH_2486), was expressed at a significantly increased level in multidrug-resistant strains. Functional inhibition experiments further implicated potential roles of CH_2486 in drug resistance. A gene spontaneously mutated in resistant strains, CH_4347, was experimentally validated to influence the morphology of spores, possibly by controlling cell wall integrity.

Project description:BACKGROUND: Candida glabrata has emerged as an important human pathogen associated with systemic and mucosal infections. Here, we describe isolation of two cholesterol-dependent Candida glabrata strains from a candidemia patient which failed to grow on the media devoid of a cholesterol source. METHODS: Both the isolates were recovered from BACTEC Plus Aerobic/F blood culture bottles of a candidemic patient. Since these isolates failed to grow on Sabouraud dextrose agar, Mueller-Hinton agar and RPMI 1640 agar media, their definitive identification required PCR sequencing of the internally transcribed spacer (ITS)1 and ITS2 regions of rDNA and the D1/D2 region sequences within 26S rRNA gene. The cholesterol auxotrophy was determined by their ability to grow on media containing a cholesterol source. The minimum inhibitory concentrations (MICs) to antifungal agents were determined by Etest. RESULTS: The identity of the isolates was confirmed by sequencing of the ITS1 and ITS2 regions of rDNA and the D1/D2 region sequences within 26S rRNA gene and also by matrix-assisted laser desorption and ionization-time-of-flight mass spectrometry with 99.9% confidence value. Both the isolates showed good growth only when media were supplemented with cholesterol, oxbile or blood. Additionally, these isolates were resistant to amphotericin B (MIC ?32 ?g/ml), fluconazole (MIC ?256 ?g/ml), voriconazole (MIC ?32 ?g/ml), itraconazole (MIC ?32 ?g/ml), and posaconazole (MIC ?32 ?g/ml), but susceptible to caspofungin (MIC range 0.064 to 0.19 ?g/ml). CONCLUSION: This appears to be the first report on isolation of cholesterol-dependent strains of C. glabrata from a candidemia patient exhibiting resistance to azoles and amphotericin B. Further, the report demonstrates that induction of cholesterol/sterol auxotrophy is associated with resistance to antifungal drugs targeting ergosterol biosynthesis. These observations may have therapeutic implications for the treatment of infections caused by such C. glabrata strains.

Dataset Information

First Genome Sequences of Two Multidrug-Resistant Candida haemulonii var. vulnera Isolates From Pediatric Patients With Candidemia.

Publications

First Genome Sequences of Two Multidrug-Resistant <i>Candida haemulonii</i> var. <i>vulnera</i> Isolates From Pediatric Patients With Candidemia.

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