The Heat Shock Transcription Factor HsfA Plays a Role in Membrane Lipids Biosynthesis Connecting Thermotolerance and Unsaturated Fatty Acid Metabolism in Aspergillus fumigatus

Abstract

Aspergillus fumigatus causes invasive pulmonary aspergillosis, a life-threatening infection accounting for high mortality rates in immunocompromised patients. The ability of this organism to grow at elevated temperatures is long recognized as an essential attribute for this mold to cause disease. A. fumigatus responds to heat stress by activating heat shock transcription factors and chaperones to orchestrate cellular responses that protect the fungus against damage caused by heat.

Unsaturated fatty acid perturbation combats emerging triazole antifungal resistance in the human fungal pathogen Aspergillus fumigatus

“…An interesting result from our MBX-7591 spectrum of activity screen is the lack of activity against other tested Aspergillus species. It seems clear that A. fumigatus possesses one functional copy of SdeA, as detailed by Fabri et al ( 42 ) and confirmed here, which is in contrast with other Aspergillus species (Table S9). Thus, one possibility to explain the MBX-7591 resistance in other Aspergillus species, if SdeA is the molecular target, is an increase in functional sdeA copy number.…”

“…S4). Strikingly, our lipid profile of MBX-7591-treated A. fumigatus cells is highly similar to the lipid profile of the conditional sdeA strain characterized by Fabri et al ( 42 ) highlighted by the increase in saturated phospholipids and decrease in monounsaturated fatty acids. Similar to oleic acid complementation of the sdeA genetic mutant strains, MBX-7591 antifungal activity is significantly reduced in the presence of oleic acid.…”

“…Similar to oleic acid complementation of the sdeA genetic mutant strains, MBX-7591 antifungal activity is significantly reduced in the presence of oleic acid. Interestingly, Fabri et al ( 42 ) reported that the sdeA conditional expression strain had wild-type levels of voriconazole and fluconazole susceptibility, which is in contrast to MBX-7591-treated A. fumigatus cells reported here ( 42 ). However, it is unclear under what assay conditions the Fabri et al experiments were conducted.…”

“…Previous and recent studies on SdeA function in fungi provide further support for the hypothesis that SdeA is a potential molecular target of MBX-7591. SdeA function was recently explored in A. fumigatus and found to be a conditionally essential gene ( 33 , 42 ). Wang et al ( 33 ) observed that loss of sdeA could partially be complemented with oleic acid and Tween 80, while Fabri et al ( 42 ) generated a conditional sdeA expression strain that could not grow in the absence of the inducer (xylose) without the addition of oleic acid.…”

“…SdeA function was recently explored in A. fumigatus and found to be a conditionally essential gene ( 33 , 42 ). Wang et al ( 33 ) observed that loss of sdeA could partially be complemented with oleic acid and Tween 80, while Fabri et al ( 42 ) generated a conditional sdeA expression strain that could not grow in the absence of the inducer (xylose) without the addition of oleic acid. We confirmed these findings with our own xylose-inducible sdeA strain (Fig.…”