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Effects of MG3290, a selective histone deacetylase inhibitor, on azole resistance in Candidaglabrata

Abstract number: 1733_1459

Yeung B., Georgopapadakou N.

Objectives: To examine whether MG3290, a highly active potentiator of azole antifungals against Aspergillus and Candida species, potentiates azoles against azole-resistant C. glabrata mutants and lowers resistance frequency when combined with azoles.

Methods: Synergy of MG3290 with azoles was determined by two-fold dilutions of each compound alone and in combination in 96-well plates (checkerboard format). Ergosterol synthesis was measured by the absorbance of lipid extracts at 281 nm; azole transport by the transport of Rhodamine123 (excitation max, 485 nm; emission max, 535 nm).

Results:C. glabrata mutants resistant to itraconazole and fluconazole were detected at 3×10-7 and 5×10-6 frequencies respectively on agar plates containing 4×MIC of the relevant azole. Mutants resistant to itraconazole/MG3290 were detected at 1×10-7 frequency on plates containing 4×MIC of itraconazole/MG3290 (none at 2×MIC), while mutants resistant to fluconazole/MG3290, at 2×10-7 frequency at 4×MIC of fluconazole/MG3290. Three of seven itraconazole- and 13 of 14 fluconazole-resistant mutants isolated and examined had altered transport and were cross resistant. Basal ergosterol levels in the azole-resistant mutants were unchanged from the parent. MG3290, at ≤4mg/mL, lowered itraconazole MICs against itraconazole-resistant mutants and fluconazole MICs against fluconazole-resistant mutants.

Conclusion: MG3290 potentiates azoles currently used in the clinic against resistant mutants and lowers resistance frequency when combined with azoles. It is therefore an attractive candidate for further development in combination with azoles.

Session Details

Date: 31/03/2007
Time: 00:00-00:00
Session name: European Society of Clinical Microbiology and Infectious Diseases
Subject:
Location: ICC, Munich, Germany
Presentation type:
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