ABCMdb

ABCB1 p.Thr591Cys

Predicted by SNAP2:	A: D (71%), C: D (75%), D: D (85%), E: D (85%), F: D (80%), G: D (85%), H: D (80%), I: D (80%), K: D (91%), L: D (80%), M: D (80%), N: D (85%), P: D (91%), Q: D (85%), R: D (91%), S: D (63%), V: D (80%), W: D (85%), Y: D (85%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, V: D, W: D, Y: D,

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Publications
[hide] Candida parapsilosis Resistance to Fluconazole: Mo... Antimicrob Agents Chemother. 2015 Oct;59(10):6581-7. doi: 10.1128/AAC.01177-15. Epub 2015 Aug 10. Souza AC, Fuchs BB, Pinhati HM, Siqueira RA, Hagen F, Meis JF, Mylonakis E, Colombo AL
Candida parapsilosis Resistance to Fluconazole: Molecular Mechanisms and In Vivo Impact in Infected Galleria mellonella Larvae.
Antimicrob Agents Chemother. 2015 Oct;59(10):6581-7. doi: 10.1128/AAC.01177-15. Epub 2015 Aug 10., [PMID:26259795]

Abstract [show]
Candida parapsilosis is the main non-albicans Candida species isolated from patients in Latin America. Mutations in the ERG11 gene and overexpression of membrane transporter proteins have been linked to fluconazole resistance. The aim of this study was to evaluate the molecular mechanisms in fluconazole-resistant strains of C. parapsilosis isolated from critically ill patients. The identities of the nine collected C. parapsilosis isolates at the species level were confirmed through molecular identification with a TaqMan qPCR assay. The clonal origin of the strains was checked by microsatellite typing. The Galleria mellonella infection model was used to confirm in vitro resistance. We assessed the presence of ERG11 mutations, as well as the expression of ERG11 and two additional genes that contribute to antifungal resistance (CDR1 and MDR1), by using real-time quantitative PCR. All of the C. parapsilosis (sensu stricto) isolates tested exhibited fluconazole MICs between 8 and 16 mug/ml. The in vitro data were confirmed by the failure of fluconazole in the treatment of G. mellonella infected with fluconazole-resistant strains of C. parapsilosis. Sequencing of the ERG11 gene revealed a common mutation leading to a Y132F amino acid substitution in all of the isolates, a finding consistent with their clonal origin. After fluconazole exposure, overexpression was noted for ERG11, CDR1, and MDR1 in 9/9, 9/9, and 2/9 strains, respectively. We demonstrated that a combination of molecular mechanisms, including the presence of point mutations in the ERG11 gene, overexpression of ERG11, and genes encoding efflux pumps, are involved in fluconazole resistance in C. parapsilosis.

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No. Sentence Comment
108 GQ302972) revealed the presence of a silent mutation (T591C) and a missense mutation (A395T) that led to a Y132F amino acid substitution and a changeintheproteinsequence(Table2).Singleallelemutations(i.e., heterozygous for the mutation) were not observed; there were only point mutations in both alleles (i.e., homozygous for the mutation). Login to comment
110 To investigate if changes in the expression patterns of the ERG11 gene, the ABC transporter TABLE 2 In vitro activities of four antifungal agents against nine clinical isolates of C. parapsilosis (sensu stricto) in the CLSI broth microdilution assay complemented by ERG11 sequence analysis and expression of the ERG11, CDR1, and MDR1 genes C. parapsilosis (sensu stricto) isolate MIC (mg/liter) Mutations in ERG11 gene Avg cDNA level (SD)a FLC VRC ANF AMB ERG11 CDR1 MDR1 LEMI 8646 8 1 2 0.25 T591C, A395T 7.4 (0.3) 9.2 (0.6) 1.5 (0.08) LEMI 8650 8 0.5 2 0.25 T591C, A395T 3.7 (0.1) 4.8 (0.1) 0.9 (0.06) LEMI 8653 16 0.5 2 0.25 T591C, A395T 1.5 (0.1) 4.0 (0.3) 0.9 (0.1) LEMI 8655 16 0.5 1 0.25 T591C, A395T 3.3 (0.2) 3.4 (0.1) 0.8 (0.2) LEMI 8657 16 0.5 2 0.125 T591C, A395T 3.9 (0.3) 3.7 (0.2) 1.0 (0.06) LEMI 8662 16 0.5 2 0.25 T591C, A395T 5.7 (0.5) 5.7 (0.5) 1.3 (0.2) LEMI 8379 8 0.5 2 0.25 T591C, A395T 4.0 (0.3) 3.3 (0.3) 0.8 (0.04) LEMI 8382 8 0.5 2 0.25 T591C, A395T 7.3 (0.4) 7.3 (0.5) 1.2 (0.06) LEMI 8383 8 0.5 1 0.25 T591C, A395T 4.4 (0.4) 7.6 (0.6) 1.0 (0.1) ATCC 22019 0.5 0.5 1 0.125 NDb 1.0 (0.00) 1.0 (0.07) 1.0 (0.07) a cDNA levels were calculated relative to average levels of cDNA obtained for the wild-type strain. Login to comment