Proteomic Perspective of Azole Resistance in Aspergillus fumigatus Biofilm Extracellular Matrix in Response to Itraconazole.

Abstract

Azole-resistant Aspergillus fumigatus makes a major challenge to the chemotherapy for invasive aspergillosis, whereas cyp51A gene mutation is the most dominant mechanism for azole resistance. Moreover, biofilm contributes to drug resistance for A. fumigatus, and extracellular matrix (ECM) is essential to protect live cells from antifungal drugs. Therefore, we performed a comparative proteomic study on the biofilm ECM of both the wild-type and azole-resistant strains of A. fumigatus under azole pressure. In total, 2377 proteins were identified, of which 480 and 604 proteins with differential expression were obtained from the wild-type and azole-resistant A. fumigatus in exposure to itraconazole respectively (fold change>2 or<0.5, P-value<0.05). We found that a high proportion of regulated proteins were located in cytoplasm, nucleus, and mitochondria. Meanwhile, GO and KEGG analyses revealed that metabolic process and ribosome pathway were significantly enriched. Particularly, differentially expressed proteins in response to azole pressure of both the wild-type and resistant strains were further analyzed. Our results indicated that these changes in biofilm ECM proteins were related to ergosterol synthesis, oxidative stress, efflux pumps, DNA repair, DNA replication, and transcription.