PMID- 30833425
OWN - NLM
STAT- Publisher
LR  - 20190406
IS  - 1098-6596 (Electronic)
IS  - 0066-4804 (Linking)
DP  - 2019 Mar 4
TI  - The contribution of clinically-derived mutations in the gene encoding the zinc
      cluster transcription factor Mrr2 to fluconazole antifungal resistance and CDR1
      expression in Candida albicans.
LID - AAC.00078-19 [pii]
LID - 10.1128/AAC.00078-19 [doi]
AB  - Mutations in the genes encoding zinc cluster transcription factors (ZCFs), such
      as TAC1, MRR1, and UPC2 play a key role in Candida albicans azole antifungal
      resistance. Artificial activation of the ZCF Mrr2 has shown increased expression 
      of the gene encoding the Cdr1 efflux pump and resistance to fluconazole. Amino
      acid substitutions in Mrr2 have recently been reported to contribute to
      fluconazole resistance in clinical isolates. In the present study, 57 C. albicans
      clinical isolates with elevated fluconazole MICs were examined for mutations in
      MRR2 and expression of CDR1 Mutations in MRR2 resulting in 15 amino acid
      substitutions were uniquely identified among resistant isolates, including 4
      substitutions (S466L, A468G, S469T, T470N) previously reported to reduce
      fluconazole susceptibility. Three additional, novel amino acid substitutions
      (R45Q, A459T, V486M) were also discovered in fluconazole-resistant isolates. When
      introduced into a fluconazole-susceptible background, no change in fluconazole
      MIC or CDR1 expression was observed for any of the mutations found in this
      collection. However, introduction of an allele leading to artificial activation
      of Mrr2 increased resistance to fluconazole as well as CDR1 expression. Moreover,
      Mrr2 amino acid changes reported previously to have the strongest effect on
      fluconazole susceptibility and CDR1 expression also exhibited no differences in
      fluconazole susceptibility or CDR1 expression relative to the parent strain.
      While all known fluconazole resistance mechanisms are represented within this
      collection of clinical isolates and contribute to fluconazole resistance to
      different extents, mutations in MRR2 do not appear to alter CDR1 expression or
      contribute to resistance in any of these isolates.
CI  - Copyright (c) 2019 American Society for Microbiology.
FAU - Nishimoto, Andrew T
AU  - Nishimoto AT
AD  - Department of Clinical Pharmacy, College of Pharmacy, University of Tennessee
      Health Science Center, Memphis, Tennessee, USA.
FAU - Zhang, Qing
AU  - Zhang Q
AD  - Department of Clinical Pharmacy, College of Pharmacy, University of Tennessee
      Health Science Center, Memphis, Tennessee, USA.
FAU - Hazlett, Brandon
AU  - Hazlett B
AD  - Department of Clinical Pharmacy, College of Pharmacy, University of Tennessee
      Health Science Center, Memphis, Tennessee, USA.
FAU - Morschhauser, Joachim
AU  - Morschhauser J
AD  - Institut fur Molekulare Infektionsbiologie, Universitat Wurzburg, Wurzburg,
      Germany.
FAU - Rogers, P David
AU  - Rogers PD
AD  - Department of Clinical Pharmacy, College of Pharmacy, University of Tennessee
      Health Science Center, Memphis, Tennessee, USA drogers@uthsc.edu.
LA  - eng
GR  - R01 AI058145/AI/NIAID NIH HHS/United States
PT  - Journal Article
DEP - 20190304
PL  - United States
TA  - Antimicrob Agents Chemother
JT  - Antimicrobial agents and chemotherapy
JID - 0315061
EDAT- 2019/03/06 06:00
MHDA- 2019/03/06 06:00
CRDT- 2019/03/06 06:00
PHST- 2019/03/06 06:00 [entrez]
PHST- 2019/03/06 06:00 [pubmed]
PHST- 2019/03/06 06:00 [medline]
AID - AAC.00078-19 [pii]
AID - 10.1128/AAC.00078-19 [doi]
PST - aheadofprint
SO  - Antimicrob Agents Chemother. 2019 Mar 4. pii: AAC.00078-19. doi:
      10.1128/AAC.00078-19.