Fluconazole susceptibility in Cryptococcus gattii is dependent on the ABC transporter Pdr11

Mai Lee Yang, John Uhrig, Kiem Vu, Anil Singapuri, Michael Dennis, Angela C Gelli, George Richard Thompson

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Cryptococcus gattii isolates from the Pacific Northwest have exhibited higher fluconazole MICs than isolates from other sites. The mechanism of fluconazole resistance in C. gattii is unknown. We sought to determine the role of the efflux pumps Mdr1 and Pdr11 in fluconazole susceptibility. Using biolistic transformation of the parent isolate, we created a strain lacking Mdr1 (mdr1 Δ) and another strain lacking Pdr11 (pdr11 Δ). Phenotypic virulence factors were assessed by standard methods (capsule size, melanin production, growth at 30 and 37°C). Survival was assessed in an intranasal murine model of cryptococcosis. Antifungal MICs were determined by the M27-A3 methodology. No differences in key virulence phenotypic components were identified. Fluconazole susceptibility was unchanged in the Mdr1 knockout or reconstituted isolates. However, fluconazole MICs decreased from 32 μg/ml for the wild-type isolate to < 0.03 μg/ml for the pdr11Δ strain and reverted to 32 μg/ml for the reconstituted strain. In murine models, no difference in virulence was observed between wild-type, knockout, or reconstituted isolates. We conclude that Pdr11 plays an essential role in fluconazole susceptibility in C. gattii. Genomic and expression differences between resistant and susceptible C. gattii clinical isolates should be assessed further in order to identify other potential mechanisms of resistance.

Original languageEnglish (US)
Pages (from-to)1202-1207
Number of pages6
JournalAntimicrobial Agents and Chemotherapy
Volume60
Issue number3
DOIs
StatePublished - Mar 1 2016

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Cryptococcus gattii
ATP-Binding Cassette Transporters
Fluconazole
Virulence
Biolistics
Northwestern United States
Cryptococcosis
Melanins
Virulence Factors
Capsules
Growth

ASJC Scopus subject areas

  • Pharmacology
  • Infectious Diseases
  • Pharmacology (medical)

Cite this

Fluconazole susceptibility in Cryptococcus gattii is dependent on the ABC transporter Pdr11. / Yang, Mai Lee; Uhrig, John; Vu, Kiem; Singapuri, Anil; Dennis, Michael; Gelli, Angela C; Thompson, George Richard.

In: Antimicrobial Agents and Chemotherapy, Vol. 60, No. 3, 01.03.2016, p. 1202-1207.

Research output: Contribution to journalArticle

Yang, Mai Lee ; Uhrig, John ; Vu, Kiem ; Singapuri, Anil ; Dennis, Michael ; Gelli, Angela C ; Thompson, George Richard. / Fluconazole susceptibility in Cryptococcus gattii is dependent on the ABC transporter Pdr11. In: Antimicrobial Agents and Chemotherapy. 2016 ; Vol. 60, No. 3. pp. 1202-1207.
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