Testing Inhibitory Drugs of the Human UPR Sensor IRE1 on Aspergillus fumigatus

Aspergillus fumigatus is a fungus that is associated with life‐threatening pulmonary infections. Unfortunately, current antifungal drugs to treat this infection are limited, making the search for novel molecular targets a high priority. A. fumigatus has an intracellular stress response pathway known as the unfolded protein response (UPR), which is key to its ability to cause infection. Inhibitors of the human UPR pathway have been developed, but are untested on A. fumigatus . Here, the ability of STF 083010 and toyocamycin, human UPR inhibitors, to inhibit the corresponding fungal UPR pathway and reduce the fitness of A. fumigatus was tested. Culturing of A. fumigatus in the presence or absence of the compound under conditions that require UPR intervention demonstrated that toyocamycin did not affect the fungus, whereas STF 083010 inhibits colony growth and is fungistatic. Additionally, STF 083010 increases the toxicity of ER stress agents and cell wall damaging agents, and it also prevents the fungus from utilizing polymeric substrates. Finally, the ability of STF 083010 to inhibit the induction of UPR target genes by a strong stimulus was examined by qPCR. The results demonstrate that STF 083010 blocks the ability of DTT to induce the expression of hacA i and bipA , indicating suppression of the fungal UPR. These results provide the first evidence that pharmacologic inhibition of the UPR pathway is feasible in A. fumigatus , and that the loss of fitness by STF 083010 could be a novel approach to antifungal therapy.