Azole Resistance of Aspergillus fumigatus Biofilms Is Partly Associated with Efflux Pump Activity
Open Access
- 1 May 2011
- journal article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 55 (5), 2092-2097
- https://doi.org/10.1128/aac.01189-10
Abstract
This study investigated the phase-dependent expression and activity of efflux pumps in Aspergillus fumigatus treated with voriconazole. Fourteen strains were shown to become increasingly resistant in the 12-h (16- to 128-fold) and 24-h (>512-fold) phases compared to 8-h germlings. An Ala-Nap uptake assay demonstrated a significant increase in efflux pump activity in the 12-h and 24-h phases (P < 0.0001). The efflux pump activity of the 8-h germling cells was also significantly induced by voriconazole (P < 0.001) after 24 h of treatment. Inhibition of efflux pump activity with the competitive substrate MC-207,110 reduced the voriconazole MIC values for the A. fumigatus germling cells by 2- to 8-fold. Quantitative expression analysis of AfuMDR4 mRNA transcripts showed a phase-dependent increase as the mycelial complexity increased, which was coincidental with a strain-dependent increase in azole resistance. Voriconazole also significantly induced this in a time-dependent manner (P < 0.001). Finally, an in vivo mouse biofilm model was used to evaluate efflux pump expression, and it was shown that AfuMDR4 was constitutively expressed and significantly induced by treatment with voriconazole after 24 h (P < 0.01). Our results demonstrate that efflux pumps are expressed in complex A. fumigatus biofilm populations and that this contributes to azole resistance. Moreover, voriconazole treatment induces efflux pump expression. Collectively, these data may provide evidence for azole treatment failures in clinical cases of aspergillosis.This publication has 38 references indexed in Scilit:
- Anti-Candida-biofilm activity of micafungin is attenuated by voriconazole but restored by pharmacological inhibition of Hsp90-related stress responsesMedical Mycology, 2010
- Regulation of multidrug resistance in pathogenic fungiFungal Genetics and Biology, 2010
- In vivobiofilm composition ofAspergillus fumigatusCellular Microbiology, 2010
- The effects of antifungal agents to conidial and hyphal forms ofAspergillus fumigatusMedical Mycology, 2010
- Time Course Global Gene Expression Analysis of an In VivoCandidaBiofilmThe Journal of Infectious Diseases, 2009
- Frequency and Evolution of Azole Resistance inAspergillus fumigatusAssociated with Treatment Failure1Emerging Infectious Diseases, 2009
- Efflux-Mediated Antifungal Drug ResistanceClinical Microbiology Reviews, 2009
- The characteristics ofAspergillus fumigatusmycetoma development: is this a biofilm?Medical Mycology, 2009
- Phase-dependent antifungal activity against Aspergillus fumigatus developing multicellular filamentous biofilmsJournal of Antimicrobial Chemotherapy, 2008
- Novel antifungal agents as salvage therapy for invasive aspergillosis in patients with hematologic malignancies: posaconazole compared with high-dose lipid formulations of amphotericin B alone or in combination with caspofunginLeukemia, 2007