Clinical azole cross-resistance in Candida parapsilosis is related to a novel MRR1 gain-of-function mutation

Branco, Joana; Ryan, Adam P.; Silva, Ana T.; Butler, Geraldine; Miranda, Isabel M.; Rodrigues, Acácio G.

doi:10.1016/j.cmi.2022.08.014

Cited by 16 publications

(11 citation statements)

References 14 publications

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“…The emergence of azole resistance in Candida species represents a major challenge to treatment [ 113 , 114 , 115 , 116 ]. Candida spp.…”

Section: Antifungals and Resistance Mechanismsmentioning

confidence: 99%

“…Recently, researchers described a new azole resistance mechanism in Candida , particularly among C. parapsilosis isolates, involving another Cdr1-like gene, the CDR1B (CPAR2_304370). Expression of a GOF mutation in the MRR1 gene impacts the fluconazole susceptibility in C. parapsilosis through CDR1B overexpression [ 114 , 127 ]. CDR1 (CLUG_03113) expression in Candida lusitaniae is also shown to be regulated by GOF mutation in MRR1 [ 128 ].…”

Section: Antifungals and Resistance Mechanismsmentioning

confidence: 99%

“…In addition, several pieces of evidence point to another mechanism involved in C. parapsilosis antifungal resistance: allele copy number variation. Our group observed an increase in the CDR1B copy number, resulting in CDR1B overexpression and a consequent reduction in fluconazole susceptibility [ 114 ]. The copy number variation mechanism has not only been associated with the drug fluconazole but also with miltefosine, a drug recently approved by the FDA for the treatment of invasive candidiasis [ 129 ].…”

Section: Antifungals and Resistance Mechanismsmentioning

confidence: 99%

See 2 more Smart Citations

Candida parapsilosis Virulence and Antifungal Resistance Mechanisms: A Comprehensive Review of Key Determinants

Branco

Miranda

Rodrigues

2023

JoF

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Candida parapsilosis is the second most common Candida species isolated in Asia, Southern Europe, and Latin America and is often involved in invasive infections that seriously impact human health. This pathogen is part of the psilosis complex, which also includes Candida orthopsilosis and Candida metapsilosis. C. parapsilosis infections are particularly prevalent among neonates with low birth weights, individuals who are immunocompromised, and patients who require prolonged use of a central venous catheter or other indwelling devices, whose surfaces C. parapsilosis exhibits an enhanced capacity to adhere to and form biofilms. Despite this well-acknowledged prevalence, the biology of C. parapsilosis has not been as extensively explored as that of Candida albicans. In this paper, we describe the molecular mechanistic pathways of virulence in C. parapsilosis and show how they differ from those of C. albicans. We also describe the mode of action of antifungal drugs used for the treatment of Candida infections, namely, polyenes, echinocandins, and azoles, as well as the resistance mechanisms developed by C. parapsilosis to overcome them. Finally, we stress the importance of the ongoing search for species-specific features that may aid the development of effective control strategies and thus reduce the burden on patients and healthcare costs.

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“…The emergence of azole resistance in Candida species represents a major challenge to treatment [ 113 , 114 , 115 , 116 ]. Candida spp.…”

Section: Antifungals and Resistance Mechanismsmentioning

confidence: 99%

Section: Antifungals and Resistance Mechanismsmentioning

confidence: 99%

Section: Antifungals and Resistance Mechanismsmentioning

confidence: 99%

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Candida parapsilosis Virulence and Antifungal Resistance Mechanisms: A Comprehensive Review of Key Determinants

Branco

Miranda

Rodrigues

2023

JoF

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“…Investigating the alignments leading to these calls showed that the CPAR2_405290 variants are likely a result of mismapping from a similar gene in the genome, so we did not investigate CPAR2_405290 further. Overexpression of CPAR2_304370 (CDR1B) has previously been observed in fluconazole-resistant isolates and shown to directly contribute to this phenotype (40,41,46). In a study investigating acquired azole resistance in consecutive isolates taken from a patient undergoing fluconazole treatment, one isolate with reduced susceptibility to fluconazole had undergone amplification of the CDR1B locus, from 4 to ~15 copies (46).…”

Section: Genome Wide Association Studymentioning

confidence: 99%

“…Overexpression of CPAR2_304370 (CDR1B) has previously been observed in fluconazole-resistant isolates and shown to directly contribute to this phenotype (40,41,46). In a study investigating acquired azole resistance in consecutive isolates taken from a patient undergoing fluconazole treatment, one isolate with reduced susceptibility to fluconazole had undergone amplification of the CDR1B locus, from 4 to ~15 copies (46). We therefore investigated the CDR1B locus in more depth.…”

Section: Genome Wide Association Studymentioning

confidence: 99%

Analysis of clinicalCandida parapsilosisisolates reveals copy number variation in key fluconazole resistance genes

Bergin,

Doorley,

Rybak

et al. 2023

Preprint

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We used whole-genome sequencing to analyse a collection of 35 fluconazole resistant and 7 susceptibleCandida parapsilosisisolates together with coverage analysis and GWAS techniques to identify new mechanisms of fluconazole resistance. Phylogenetic analysis shows that although the collection is diverse, two probable outbreak groups were identified. We identified copy number variation of two genes,ERG11andCDR1B, in resistant isolates. Two strains have a CNV at theERG11locus; the entire ORF is amplified in one, and only the promoter region is amplified in the other. We show the annotated telomeric geneCDR1Bis actually an artefactualin silicofusion of two highly similar neighbouringCDRgenes due to an assembly error in theC. parapsilosisCDC317 reference genome. We report highly variable copy numbers of theCDR1Bregion across the collection. Several strains have increased expansion of the two genes into a tandem array of new chimeric genes. Other strains have experienced a deletion between the two genes creating a single gene with a reciprocal chimerism. We find translocations, duplications, and gene conversion across theCDRgene family in theC. parapsilosisspecies complex, showing that it is a highly dynamic family.

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An open call to join the CMI editorial team: editor in fungal infections

Leibovici¹

2023

Clinical Microbiology and Infection

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Clinical azole cross-resistance in Candida parapsilosis is related to a novel MRR1 gain-of-function mutation

Cited by 16 publications

References 14 publications

Candida parapsilosis Virulence and Antifungal Resistance Mechanisms: A Comprehensive Review of Key Determinants

Candida parapsilosis Virulence and Antifungal Resistance Mechanisms: A Comprehensive Review of Key Determinants

Analysis of clinicalCandida parapsilosisisolates reveals copy number variation in key fluconazole resistance genes

An open call to join the CMI editorial team: editor in fungal infections

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