Regulation of Azole Resistance in Aspergillus fumigatus

Aspergillus fumigatus is the most important airborne mould pathogen and allergen worldwide. Estimates suggest that over 3 million people have invasive or chronic infections that lead to in excess of 600,000 deaths every year. Very few drugs are available to treat the various forms of aspergillosis and we rely predominantly on the azole class of agents (Itraconazole, Voriconazole, Posoconazole and the recently licensed Isavuconazole). Resistance to the azoles is emerging. For individuals that are infected with a resistant isolate the mortality rate exceeds 88%. Therapy failure is in part attributed to delays in administering alternative therapies so methods to rapidly detect resistance is critical. While resistance in around 50% of clinical isolates has been linked to modification of the gene encoding the target of the azoles, cyp51A, our understanding of what leads to resistance in the remaining strains is lacking.

We have undertaken a programme of work to identify transcriptional and post transcriptional regulators of azole resistance. We have discovered a cohort of transcription factors and kinases including the CCAAT-binding complex, Negative Cofactor 2 and ssn3 that modulate azole tolerability. With a view to understanding which genes are directly regulated by these transcription factors, we have performed genome-wide protein-DNA interaction analysis using ChIP-seq. We have identified that these transcription factors bind the promoters of genes known to be associated with azole tolerance including cyp51A the drug transporter cdr1B. Our Chip-seq data provides evidence to suggest that these regulators bind the promoters of many genes however do not always modulate their expression. We are currently exploring the role of ssn3 and a number of other kinases in the regulation of azole resistance.