ABCA1 p.Thr1389Cys
| Predicted by SNAP2: | A: D (63%), C: D (66%), D: D (71%), E: D (80%), F: D (80%), G: D (75%), H: D (80%), I: D (75%), K: D (85%), L: D (75%), M: D (66%), N: D (66%), P: D (85%), Q: D (75%), R: D (85%), S: N (66%), V: D (53%), W: D (85%), Y: D (71%), |
| Predicted by PROVEAN: | A: N, 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: N, V: D, W: D, Y: D, |
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[hide] In vivo and in vitro acquisition of resistance to ... Antimicrob Agents Chemother. 2014 Aug;58(8):4604-11. doi: 10.1128/AAC.02603-14. Epub 2014 May 27. Ricardo E, Miranda IM, Faria-Ramos I, Silva RM, Rodrigues AG, Pina-Vaz C
In vivo and in vitro acquisition of resistance to voriconazole by Candida krusei.
Antimicrob Agents Chemother. 2014 Aug;58(8):4604-11. doi: 10.1128/AAC.02603-14. Epub 2014 May 27., [PMID:24867987]
Abstract [show]
Candida krusei is an important agent of opportunistic infections that often displays resistance to several antifungals. We describe here the in vivo acquisition of resistance to voriconazole (VRC) by C. krusei isolates recovered from a leukemia patient during a long period of VRC therapy. In order to mimic the in vivo development of VRC resistance, a susceptible C. krusei isolate was exposed daily to 1 mug/ml of VRC in vitro. Interestingly, after 5 days of exposure to VRC, a MIC of 4 mug/ml was achieved; this value remained constant after 25 additional days of treatment with VRC and also after 30 consecutive days of incubation in VRC-free medium. Our objective was to determine the associated molecular resistance mechanisms, such as expression of efflux pump genes and ERG11 gene mutations, among the resistant strains. Synergistic effects between the efflux blocker tacrolimus (FK506) and VRC were found in all of the resistant strains. Moreover, ABC1 gene expression increased over time in both the in vivo- and in vitro-induced resistant strains, in contrast to the ABC2 and ERG11 genes, whose expression was invariably lower and constant. ERG11 gene sequencing showed two different types of mutations, i.e., heterozygosity at T1389T/C, corresponding to synonymous mutations, in C. krusei strains and a missense mutation at position T418C, resulting in a change from Tyr to His, among resistant C. krusei clinical isolates. This study highlights the relevance of ATP-dependent efflux pump (namely, Abc1p) activity in VRC resistance and describes new mutations in the ERG11 gene among resistant C. krusei clinical isolates.
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194 On the other hand, the heterozygous alteration detected (T1389C), which is located outside the azole binding site, according to previously published data, was found in both susceptible and resistant strains (32).
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ABCA1 p.Thr1389Cys 24867987:194:57
status: NEW[hide] Overexpression of Both ERG11 and ABC2 Genes Might ... PLoS One. 2015 Aug 26;10(8):e0136185. doi: 10.1371/journal.pone.0136185. eCollection 2015. He X, Zhao M, Chen J, Wu R, Zhang J, Cui R, Jiang Y, Chen J, Cao X, Xing Y, Zhang Y, Meng J, Deng Q, Sui T
Overexpression of Both ERG11 and ABC2 Genes Might Be Responsible for Itraconazole Resistance in Clinical Isolates of Candida krusei.
PLoS One. 2015 Aug 26;10(8):e0136185. doi: 10.1371/journal.pone.0136185. eCollection 2015., [PMID:26308936]
Abstract [show]
OBJECTIVE: To study the main molecular mechanisms responsible for itraconazole resistance in clinical isolates of Candida krusei. METHODS: The 14alpha-demethylases encoded by ERG11 gene in the 16 C.krusei clinical isolates were amplified by polymerase chain reaction (PCR), and their nucleotide sequences were determined to detect point mutations. Meanwhile, ERG11 and efflux transporters (ABC1 and ABC2) genes were determined by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) for their expression in itraconazole-resistant (R), itraconazole-susceptible dose dependent (SDD) and itraconazole-susceptible (S) C.krusei at the mRNA level. RESULTS: We found 7-point mutations in ERG11 gene of all the C.krusei clinical isolates, including 6 synonymous mutations and 1 missense mutation (C44T). However, the missense mutation was found in the three groups. The mRNA levels of ERG11 gene in itraconazole-resistant isolates showed higher expression compared with itraconazole-susceptible dose dependent and itraconazole-susceptible ones (P = 0.015 and P = 0.002 respectively). ABC2 gene mRNA levels in itraconazole-resistant group was significantly higher than the other two groups, and the levels of their expression in the isolates appeared to increase with the decrease of susceptibility to itraconazole (P = 0.007 in SDD compared with S, P = 0.016 in SDD with R, and P<0.001 in S with R respectively). While ABC1 gene presented lower expression in itraconazole resistant strains. However, the mRNA levels of ERG11, ABC1 and ABC2 in a C.krusei (CK10) resistant to both itraconazole and voriconazole were expressed highest in all the itraconazole-resistant isolates. CONCLUSIONS: There are ERG11 gene polymorphisms in clinical isolates of C.krusei. ERG11 gene mutations may not be involved in the development of itraconazole resistance in C.krusei. ERG11 and ABC2 overexpression might be responsible for the acquired itraconazole resistance of these clinical isolates.
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131 The 6 synonymous mutations can appear in both non-resistant and resistant strains, and all the C.krusei strains presented C642T, T1389C, and G1536C mutations.
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ABCA1 p.Thr1389Cys 26308936:131:129
status: NEW202 Our data showed that there were 7-point mutations existing in ERG11 gene of C. krusei, including 6 synonymous mutations (C51T, C642T, A756T, T939C, T1389C, and G1536C) and 1 missense mutation (C44T).
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ABCA1 p.Thr1389Cys 26308936:202:148
status: NEW205 Moreover, in our study, all the non-resistant and resistant C.krusei strains presented C642T, T1389C, G1536C mutations.
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ABCA1 p.Thr1389Cys 26308936:205:94
status: NEW206 Ricardo et al. [19] also reported that T1389C mutation occurred in all the experimental strains.
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ABCA1 p.Thr1389Cys 26308936:206:39
status: NEW134 The 6 synonymous mutations can appear in both non-resistant and resistant strains, and all the C.krusei strains presented C642T, T1389C, and G1536C mutations.
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ABCA1 p.Thr1389Cys 26308936:134:129
status: NEW208 Our data showed that there were 7-point mutations existing in ERG11 gene of C. krusei, including 6 synonymous mutations (C51T, C642T, A756T, T939C, T1389C, and G1536C) and 1 missense mutation (C44T).
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ABCA1 p.Thr1389Cys 26308936:208:148
status: NEW211 Moreover, in our study, all the non-resistant and resistant C.krusei strains presented C642T, T1389C, G1536C mutations.
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ABCA1 p.Thr1389Cys 26308936:211:94
status: NEW212 Ricardo et al. [19] also reported that T1389C mutation occurred in all the experimental strains.
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ABCA1 p.Thr1389Cys 26308936:212:39
status: NEW