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DIA-Based Quantitative Proteomic Analysis of Early and Late Endosomes in A549 Cells Following Amphotericin B Pretreatment and Influenza A Virus Infection

ABSTRACT: Amphotericin B (AmB) is a polyene macrolide antifungal agent that binds to ergosterol, disrupting fungal membranes through lipid interactions. However, its effects on host cell protein composition remain unclear. In this study, A549 cells were pretreated with AmB prior to infection with the influenza A virus, and early and late endosomal fractions were isolated. DIA-based quantitative proteomics revealed that AmB alters the protein composition of endosomes during infection, suggesting that it modulates endosomal protein dynamics in virus-infected cells.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Influenza

SUBMITTER: Di He

LAB HEAD: Bin Cao

PROVIDER: PXD064637 | Pride | 2026-02-02

REPOSITORIES: Pride

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			Action	DRS
	PAmBEE1.raw	Raw
	PAmBEE2.raw	Raw
	PAmBEE3.raw	Raw
	PAmBLE1.raw	Raw
	PAmBLE2.raw	Raw

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Shotgun Proteomic Identification of Amphotericin B Targets in Late Endosomes of Influenza A Virus-Infected A549 Cells

Project description:Amphotericin B (AmB), a polyene macrolide antifungal, is well known for its ability to bind ergosterol and cholesterol; however, its interactions with host proteins remain poorly characterized. In this study, we aimed to identify AmB-binding targets in A549 cells infected with the influenza A virus (H1N1) strain A/PR/8/34 (PR8). We isolated late endosomal fractions and performed a biotin–streptavidin pulldown using a biotinylated AmB probe, with specificity confirmed by competition with excess free AmB. The proteins enriched from these fractions were then analyzed by shotgun LC–MS/MS, revealing a set of late endosomal proteins that specifically interact with AmB during influenza A virus infection.

2026-02-02 | PXD064601 | Pride

Effect of amphotericin B on Aspergillus fumigatus

Project description:Amphotericin B (AMB) is the most widely used polyene antifungal drug for the treatment of systemic fungal infections including invasive aspergillosis. We aimed to understand molecular targets of AMB in Aspergillus fumigatus (Afu) by genomic approaches. Amphotericin B (AMB) is the most widely used polyene antifungal drug for the treatment of systemic fungal infections including invasive aspergillosis. We aimed to understand molecular targets of AMB in Aspergillus fumigatus (Afu) by microarray and proteomic methods. Keywords: Aspergillus fumigatus treated with amphotericin B for 24 hours Experiment was performed in dye swap manner from two different biological replicates

2010-05-26 | E-GEOD-10505 | biostudies-arrayexpress

Effect of amphotericin B on Aspergillus fumigatus

2008-02-14 | GSE10505 | GEO

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

Project description: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.

2025-05-05 | PXD056876 | Pride

Analysis of the Aspergillus fumigatus proteomic response to amphotericin B (AmB) reveals involvement of the Rta1-like protein RtaA in resistance

Project description:The filamentous fungus Aspergillus fumigatus is an opportunistic human pathogen, which can cause mycoses and allergies in susceptible individuals. With regard to therapy, the polyene drug amphotericin B (AmB) is still frequently used to treat Aspergillus fumigatus infections due to the fact that it remains effective against azole-resistant Aspergillus strains. AmB binds to ergosterol in the fungal membrane, but its mode of action and the fungal resistance mechanisms involved have not been completely elucidated yet. To get further insights into the drug mechanisms of AmB, we investigated the proteomic profile of A. fumigatus in response to AmB and its liposomal formulation by LC-MS/MS analysis. A significant increase (≥ 2-fold) in abundance of 202 different proteins in response to AmB and 193 in case of liposomal AmB was observed, while the level of 70 and 83 proteins decreased, respectively. In particular, the level of proteins anchored to the membrane, involved in catabolic processes, aromatic acid degradation, or secondary metabolism increased prominently. Of particular note was the more than 300-fold increase of a RTA1 domain-containing protein after AmB treatment. Fungal RTA-like proteins represent lipid-translocating exporters, which are characterized by multiple transmembrane regions and often confer resistance to toxic chemicals. Indeed, the deletion of the corresponding gene in A. fumigatus led to an increased susceptibility to AmB and other antifungal polyenes such as nystatin. Particularly worthy of mention is that some of the most significantly increased proteins included enzymes involved in the biosynthesis of secondary metabolites such as the prenylated polyphenol fumicycline as well as xanthocillin and hexadehydro-astechrome, which both form complexes with transition metals.

2025-01-06 | PXD042190 | Pride

Comparative Transcriptomics Reveal Determinants of Amphotericin B Resistance in Candida auris

Project description:Candida auris is an emerging multidrug-resistant human fungal pathogen often refractory to treatment by all classes of antifungal drugs. Amphotericin B (AmB) is a fungicidal drug that, despite its toxic side effects, remains a drug of choice for the treatment of drug-resistant fungal infections, including those caused by C. auris. However, the molecular mechanisms underlying AmB resistance are poorly understood. In this study, we present data that suggests membrane lipid alterations and chromatin modifications are critical processes that contribute to or cause adaptive AmB resistance in clinical C. auris isolates. To determine the plausible cause of increased AmB resistance, we performed RNA-seq of AmB-resistant and sensitive C. auris isolates. Remarkably, AmB-resistant strains show a pronounced enrichment of genes involved in lipid and ergosterol biosynthesis, adhesion, drug transport as well as chromatin remodeling. The transcriptomics data confirm increased adhesion and reduced lipid membrane permeability of AmB-resistant strains compared to the sensitive isolates. The AmB-resistant strains also display hyper-resistance to cell wall perturbing agents, including congo red, calcofluor white and caffeine. Additionally, we noticed an increased phosphorylation of Mkc1 cell integrity MAP kinase upon AmB treatment. Collectively, these data identify differences in the transcriptional landscapes of AmB-resistant vs AmB-senstive isolates, and provide a framework for the mechanistic understanding of AmB resistance in C. auris.

2022-05-02 | GSE190920 | GEO

Overcoming amphotericin B resistance in Candida auris using the antiemetic drug, rolapitant

Project description:The emergence of Candida auris poses a significant health challenge that has led to a new era of multidrug-resistant fungal infections. Invasive infections caused by C. auris are usually associated with remarkable morbidity and mortality. For many years, amphotericin B (AmB) remained the most efficient and the last line of treatment against most hard-to-treat fungal infections. However, strains of C. auris possess extraordinary resistance to most antifungal agents, including AmB. In this study, we screened ~2600 FDA-approved drugs and clinical compounds to identify the antiemetic drug rolapitant as a promising enhancer to AmB against C. auris. Rolapitant exhibited potent synergistic interactions with AmB against all tested (29/29) C. auris isolates. In a time-kill assay, rolapitant restored the fungicidal activity of AmB within 4 h. Additionally, the synergistic relationship between rolapitant and AmB was observed against other medically crucial Candida, Cryptococcus and Aspergillus species with ΣFICI that ranged from 0.16 to 0.5. In a transcriptomic study, ion transporters and ATP generation were identified as primary pathways impacted in C. auris AR0390 cells exposed to rolapitant. An ATP luminescence assay confirmed that rolapitant, at sub-inhibitory concentrations, significantly interfered with ATP production in C. auris. Moreover, rolapitant enhanced the in vivo activity of AmB in a mouse model of disseminated C. auris infection, as the combination reduced the fungal burden in murine kidneys by ~1 log (~90%) colony forming units. Our findings warrant further investigation of using rolapitant to overcome AmB resistance in C. auris and other fungal species.

2024-09-26 | GSE263806 | GEO

Expression profiling of T. rubrum treated with amphotericin B and ketoconazole

Project description:Two antifungal agents, ketoconazole (KTZ) and amphotericin B (AMB), have specific activity against dermatophytes.A cDNA microarray was constructed from the expressed sequence tags (ESTs) of different developmental stages, and transcriptional profiles of the responses to KTZ and AMB were determined. Some class-specific and mechanism-independent changes in gene expression were found. Keywords: comparison of expression status

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Brain glucose induces tolerance of Cryptococcus neoformans to amphotericin B during meningitis

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NS1-mediated inhibition of c-Abl results in acute lung injury and priming for bacterial co-infections; insights into 1918 H1N1 pandemic

Project description:NS1 proteins from avian influenza viruses like the 1918 pandemic NS1 are capable of inhibiting the key signaling integrator c-Abl (Abl1), resulting in massive cytopathic cell alterations. In the current study, we addressed the consequences of NS1-mediated alteration of c-Abl on acute lung injury and pathogenicity. Comparing isogenic strains that differ only in their ability to inhibit c-Abl, we observed elevated pathogenicity for the c-Abl-inhibiting virus. NS1-mediated block of c-Abl resulted in severe lung pathology and massive edema formation and facilitated secondary bacterial pneumonia. This phenotype was independent of differences in replication and immune responses, defining it as an NS1 virulence mechanism distinct from its canonical functions. Microarray analysis revealed extensive down-regulation of genes involved in cell integrity and vascular endothelial regulation. In conclusion, NS1 protein-mediated blockade of c-Abl signaling drives acute lung injury and primes for bacterial co-infections revealing potential insights into the pathogenicity of the 1918 pandemic virus. Lung transcription analysis of Influenza A virus infected mice.

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