An Alanine Aminotransferase Is Required for Biofilm-Specific Resistance of Aspergillus fumigatus to Echinocandin Treatment

Abstract

Aspergillus fumigatus is a ubiquitous filamentous fungus that causes an array of diseases depending on the immune status of an individual, collectively termed aspergillosis. Antifungal therapy for invasive pulmonary aspergillosis (IPA) or chronic pulmonary aspergillosis (CPA) is limited and too often ineffective.

Filamentous fungal biofilms: Conserved and unique aspects of extracellular matrix composition, mechanisms of drug resistance and regulatory networks in Aspergillus fumigatus

“…In addition, low-oxygen stress can modify primary metabolic pathways, including the down-regulation of the TCA cycle, induction of glycolysis as well as alanine, aspartate, glutamate metabolism 84 . Consistent with this hypothesis, it was recently reported that an alanine aminotransferase, AlaA, was involved in the resistance of A. fumigatus biofilms to echinocandin treatment 89 . However, growth of A. fumigatus in a low-oxygen environment is not sufficient to promote antifungal drug resistance, which indicated that other features of filamentous fungal biofilms may also be required to contribute to antimicrobial drug resistance 90 , 91 .…”

Assessing the intracellular primary metabolic profile of Trichoderma reesei and Aspergillus niger grown on different carbon sources

“…The alanine backbone is still believed to be incorporated into the formation of stable cell components, such as cell walls and membranes ( Gunina et al., 2014 ). Finally, the importance of alanine in the microbial central metabolism is not limited to its role as a nitrogen and carbon source, but also by participating in cell response against salt stress ( Ding et al., 2019 ), acting like a nitrogen sink for ammonium accumulation ( Kerkaert et al., 2022 ), and even being an active player in the coordination of bacterial biofilms ( Díaz-Pascual et al., 2021 ).…”

“…Arginine, when cleaved by arginase, is converted into ornithine upon release of urea. Ornithine serves as a precursor to polyamine biosynthesis, and threonine to glycine biosynthesis ( Kanehisa et al., 2021 ; Kerkaert et al., 2022 ). The accumulation of these amino acids in A. niger seems to be important for the fungal growth and adaptation in this carbon source.…”

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

“…Aside from some likely alterations in the cell permeability, which may account for different levels of drug uptake, our results point out a potential synergy between echinocandins and inhibition of monounsaturated FA synthesis, which specifically increases the efficacy of this antifungal against the biofilm state found in established infection of most filamentous fungi. Examples of molecules and determinants of virulence that sustain this concept are increasingly relevant in A. fumigatus ( 61 , 62 ). We also demonstrated that inhibiting FA synthase strikingly altered the localization pattern of SdeA, since the granular structures following trans-chalcone treatment are specific to SdeA and significantly large to be considered stress granules observed in aspergilli ( 63 ).…”