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The proteomic response of Aspergillus fumigatus wildtype and rtaA knockout strain to Amphotericin B

ABSTRACT: Amphotericin B (AmB) and AmBisome are vital treatments for invasive fungal infections, particularly invasive aspergillosis caused by Aspergillus fumigatus spores. However, increasing resistance to AmB in clinical isolates of A. fumigatus is a growing concern. Despite this, the mechanisms of AmB resistance in A. fumigatus remain unclear. In this study, we conducted a proteomic analysis of A. fumigatus exposed to sublethal concentrations of AmB and AmBisome, identifying proteins that were strongly induced by these drugs. One of the most upregulated proteins was RtaA, which encodes a member of the RTA-like protein family, that comprises conserved fungal membrane proteins with putative functions as transporters or translocases. We found that deleting rtaA led to increased polyene sensitivity and overexpression to modest resistance and is mainly located in plasma and partially vacuolar membranes. Interestingly, rtaA expression was only induced by exposure to AmB and nystatin, but not by other antifungals such as itraconazole and caspofungin. Deletion of rtaA did not significantly change the ergosterol content of A. fumigatus, but decreased fluorescence intensity of the sterol-binding stain filipin. This suggests that RtaA is involved in sterol and lipid trafficking, possibly by transporting the target ergosterol from or to lipid droplets. These findings reveal a novel polyene resistance mechanism that warrants further investigation to determine its exact mechanism and importance in clinical resistant isolates of A. fumigatus.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Aspergillus Fumigatus Cea17

SUBMITTER: Thomas Krüger

LAB HEAD: Axel A. Brakhage

PROVIDER: PXD056876 | Pride | 2025-05-05

REPOSITORIES: Pride

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The proteomic response of Aspergillus fumigatus to amphotericin B (AmB) reveals the involvement of the RTA-like protein RtaA in AmB resistance.

Abou-Kandil Ammar A Tröger-Görler Sophie S Pschibul Annica A Krüger Thomas T Rosin Maira M Schmidt Franziska F Akbarimoghaddam Parastoo P Sarkar Arjun A Cseresnyés Zoltán Z Shadkchan Yana Y Heinekamp Thorsten T Gräler Markus H MH Barber Amelia E AE Walther Grit G Figge Marc Thilo MT Brakhage Axel A AA Osherov Nir N Kniemeyer Olaf O

microLife 20241205

The polyene antimycotic amphotericin B (AmB) and its liposomal formulation AmBisome belong to the treatment options of invasive aspergillosis caused by Aspergillus fumigatus. Increasing resistance to AmB in clinical isolates of Aspergillus species is a growing concern, but mechanisms of AmB resistance remain unclear. In this study, we conducted a proteomic analysis of A. fumigatus exposed to sublethal concentrations of AmB and AmBisome. Both antifungals induced significantly ...[more]

PMID: 39790482

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Project description:Aspergillus fumigatus can cause Invasive Pulmonary Aspergillosis (IPA), the most severe form of Aspergillus-related infections. Fungicidal azoles and fungistatic caspofungin (CAS) are the first- and second-line therapies, respectively, used to treat IPA. However, azole-resistance is on the rise and new therapeutic alternatives need to be implemented. Recently, we showed that treatment of A. fumigatus with CAS or micafungin, but not voriconazole, induces production of the oxylipin 5,8-diHODE by the fungal oxygenase PpoA. Here we investigated the influence of ppo genes, that encode fatty acid oxygenases responsible for oxylipin biosynthesis, on CAS tolerance. The ppo mutants showed a very complex pattern of CAS susceptibility. PpoA and PpoC influence on CAS tolerance is mediated by MpkA phosphorylation and protein kinase A (PKA) activity. RNAseq transcriptional profiling and label-free quantitative proteomics (spectral counts) of the ppoA, and ppoC mutants showed that differentially expressed genes and proteins are related to secondary metabolites and carbohydrate metabolism. We tested several mutants of these differentially expressed genes encoding transcription factors and signal transduction proteins and some of them are more susceptible to CAS. We also characterized two clinical isolates, CNM7555 and IFM41607, that have decreased and increased susceptibility to CAS. CNM7555 does not have increased oxylipin production in the presence of CAS while the oxylipin induction upon CAS exposure is increased in the IFM41607, suggesting oxylipins are not the single mechanism involved in CAS tolerance in these isolates. Upon CAS exposure, CNM7555 has increased MpkA phosphorylation and PKA activity than IFM41607. Modulation of secondary metabolite production and carbohydrate metabolism is also essential in these clinical isolates for acquiring CAS tolerance. Our results reveal different aspects and genetic determinants involved in A. fumigatus CAS tolerance.

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Dataset Information

The proteomic response of Aspergillus fumigatus wildtype and rtaA knockout strain to Amphotericin B

Dataset's files

Publications

The proteomic response of <i>Aspergillus fumigatus</i> to amphotericin B (AmB) reveals the involvement of the RTA-like protein RtaA in AmB resistance.

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