Impact of ERG3 mutations and expression of ergosterol genes controlled by UPC2 and NDT80 in Candida parapsilosis azole resistance

Branco, Joana; Ola, Mihaela; Silva, R.M.; Fonseca, Elza; Araújo‐Gomes, Nuno; Martins-Cruz, Cláudia; Silva, Ana T.; Silva-Dias, Ana; Pina-Vaz, Cidália; Erraught, C.; Brennan, Lorraine; Rodrigues, Acácio G.; Butler, Geraldine; Miranda, Isabel M.

doi:10.1016/j.cmi.2017.02.002

Cited by 46 publications

(32 citation statements)

References 45 publications

(55 reference statements)

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“…Our finding of an ERG3 mutation as a cause of azole resistance in this clinical isolate is supported by the recent work of Branco et al (31). In that study, a C. parapsilosis strain FIG 2 Schematic representation of RNA and whole-genome sequencing data for isolate 2 compared to isolate 1.…”

Section: Discussionsupporting

confidence: 85%

Loss of C-5 Sterol Desaturase Activity Results in Increased Resistance to Azole and Echinocandin Antifungals in a Clinical Isolate of Candida parapsilosis

Rybak

Dickens

Parker

et al. 2017

Antimicrob Agents Chemother

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Among emerging non- species, is of particular concern as a cause of nosocomial bloodstream infections in neonatal and intensive care unit patients. While fluconazole and echinocandins are considered effective treatments for such infections, recent reports of fluconazole and echinocandin resistance in indicate a growing problem. The present study describes a novel mechanism of antifungal resistance in this organism affecting susceptibility to azole and echinocandin antifungals in a clinical isolate obtained from a patient with prosthetic valve endocarditis. Transcriptome analysis indicated differential expression of several genes in the resistant isolate, including upregulation of ergosterol biosynthesis pathway genes ,, ,, ,, and Whole-genome sequencing revealed that the resistant isolate possessed an mutation resulting in a G111R amino acid substitution. Sterol profiles indicated a reduction in sterol desaturase activity as a result of this mutation. Replacement of both mutant alleles in the resistant isolate with the susceptible isolate's allele restored wild-type susceptibility to all azoles and echinocandins tested. Disruption of in the susceptible and resistant isolates resulted in a loss of sterol desaturase activity, high-level azole resistance, and an echinocandin-intermediate to -resistant phenotype. While disruption of in resulted in azole resistance, echinocandin MICs, while elevated, remained within the susceptible range. This work demonstrates that the G111R substitution in Erg3 is wholly responsible for the altered azole and echinocandin susceptibilities observed in this isolate and is the first report of an mutation influencing susceptibility to the echinocandins.

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Section: Discussionsupporting

confidence: 85%

Loss of C-5 Sterol Desaturase Activity Results in Increased Resistance to Azole and Echinocandin Antifungals in a Clinical Isolate of Candida parapsilosis

Rybak

Dickens

Parker

et al. 2017

Antimicrob Agents Chemother

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“…Further studies revealed that both Cdr1 and Mdr1 in this species are only partially required for decreased azole susceptibility, as disruption of the corresponding genes resulted in only a mild decrease in fluconazole MICs (281). These studies suggest that there is often a combination of molecular mechanisms, including sterol and efflux pump gene alterations, responsible for resistance in C. parapsilosis (133,283,296).…”

Section: Antifungal Susceptibility and Resistancementioning

confidence: 84%

“…Gácser et al (17) applied the C. albicans constructs directly to C. parapsilosis, whereas Ding and Butler (18) adapted it by replacing the promoters driving the expression of SAT1 and FLP with the orthologous sequences from C. parapsilosis. The SAT1 flipper cassette has since been used to delete several genes in C. parapsilosis (60,(126)(127)(128)(129)(130)(131)(132)(133).…”

Section: Genetic Toolboxmentioning

confidence: 99%

Candida parapsilosis: from Genes to the Bedside

et al. 2019

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SUMMARY Patients with suppressed immunity are at the highest risk for hospital-acquired infections. Among these, invasive candidiasis is the most prevalent systemic fungal nosocomial infection. Over recent decades, the combined prevalence of non-albicans Candida species outranked Candida albicans infections in several geographical regions worldwide, highlighting the need to understand their pathobiology in order to develop effective treatment and to prevent future outbreaks. Candida parapsilosis is the second or third most frequently isolated Candida species from patients. Besides being highly prevalent, its biology differs markedly from that of C. albicans, which may be associated with C. parapsilosis’ increased incidence. Differences in virulence, regulatory and antifungal drug resistance mechanisms, and the patient groups at risk indicate that conclusions drawn from C. albicans pathobiology cannot be simply extrapolated to C. parapsilosis. Such species-specific characteristics may also influence their recognition and elimination by the host and the efficacy of antifungal drugs. Due to the availability of high-throughput, state-of-the-art experimental tools and molecular genetic methods adapted to C. parapsilosis, genome and transcriptome studies are now available that greatly contribute to our understanding of what makes this species a threat. In this review, we summarize 10 years of findings on C. parapsilosis pathogenesis, including the species’ genetic properties, transcriptome studies, host responses, and molecular mechanisms of virulence. Antifungal susceptibility studies and clinician perspectives are discussed. We also present regional incidence reports in order to provide an updated worldwide epidemiology summary.

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“…Y132F and K143R are presumably the most frequently identified amino acid changes causing FLZR and/or VRZR, and we noticed that isolates harboring Y132F in Erg11p are significantly associated with a mortality rate that is higher than that associated with Y132F+K143R isolates [170]. Beyond the common paradigm of ERG11 and efflux pump involvement in azole resistance, whole genome sequence analysis showed that a laboratory-driven, posaconazole-resistant C. parapsilosis isolate harbored an amino acid substitution in Erg3, R135I, which is believed to confer azole resistance and prevent the formation of toxic sterol intermediates [188].…”

Section: Candida Parapsilosismentioning

confidence: 89%

The Quiet and Underappreciated Rise of Drug-Resistant Invasive Fungal Pathogens

Arastehfar

Lass‐Flörl

Garcia-Rubio

et al. 2020

JoF

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Human fungal pathogens are attributable to a significant economic burden and mortality worldwide. Antifungal treatments, although limited in number, play a pivotal role in decreasing mortality and morbidities posed by invasive fungal infections (IFIs). However, the recent emergence of multidrug-resistant Candida auris and Candida glabrata and acquiring invasive infections due to azole-resistant C. parapsilosis, C. tropicalis, and Aspergillus spp. in azole-naïve patients pose a serious health threat considering the limited number of systemic antifungals available to treat IFIs. Although advancing for major fungal pathogens, the understanding of fungal attributes contributing to antifungal resistance is just emerging for several clinically important MDR fungal pathogens. Further complicating the matter are the distinct differences in antifungal resistance mechanisms among various fungal species in which one or more mechanisms may contribute to the resistance phenotype. In this review, we attempt to summarize the burden of antifungal resistance for selected non-albicansCandida and clinically important Aspergillus species together with their phylogenetic placement on the tree of life. Moreover, we highlight the different molecular mechanisms between antifungal tolerance and resistance, and comprehensively discuss the molecular mechanisms of antifungal resistance in a species level.

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Impact of ERG3 mutations and expression of ergosterol genes controlled by UPC2 and NDT80 in Candida parapsilosis azole resistance

Cited by 46 publications

References 45 publications

Loss of C-5 Sterol Desaturase Activity Results in Increased Resistance to Azole and Echinocandin Antifungals in a Clinical Isolate of Candida parapsilosis

Loss of C-5 Sterol Desaturase Activity Results in Increased Resistance to Azole and Echinocandin Antifungals in a Clinical Isolate of Candida parapsilosis

Candida parapsilosis: from Genes to the Bedside

The Quiet and Underappreciated Rise of Drug-Resistant Invasive Fungal Pathogens

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