Milbemycins: more than efflux inhibitors for fungal pathogens
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PROVIDER: PRJNA173240 | ENA |
REPOSITORIES: ENA
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Project description:This study investigated the effect of milbemycons as efflux inhibitors and antifungal agents. Milbemycin oxims can inhibit growth of Candida glabrata and C. albicans. The effect of milbemycins on transcriptomes was inbvestigated.
2013-03-08 | GSE40232 | GEO
Project description:This study investigated the effect of milbemycons as efflux inhibitors and antifungal agents. Milbemycin oxims can inhibit growth of Candida glabrata and C. albicans. The effect of milbemycins on transcriptomes was inbvestigated. Gene expression was measured in C. glabrata milbemycin-treated cells (1h) and compared to untreated cells in the incubation mediun RPMI. The one-color system was used. Four biological replicates were used for each condition. Gene expression was measured in C. albicans milbemycin-treated cells (1h) and compared to untreated cells in the incubation mediun RPMI. The one-color system was used. Three biological replicates were used for each condition.
2013-03-08 | E-GEOD-40232 | biostudies-arrayexpress
Project description:Repurposing bioactive aporphine alkaloids as efflux pump inhibitors
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Project description:Antibiotic resistance continues to rise as a global health threat. Novel anti-virulence strategies diminish the drive for evolutionary pressure, but still hinder a pathogen’s ability to infect a host. Treatment of the highly virulent Pseudomonas aeruginosa strain PA14 with virulence inhibitors (R-2 and R-6) elicited widely varying transcriptional profiles. Of interest, expression of a family of resistance-nodulation-division (RND) efflux pumps implicated in the intrinsic drug resistance of P. aeruginosa, was significantly altered by R-2 and R-6 treatment. While structurally similar, these inhibitors caused differential expression of various RND efflux pumps within the Mex family—R-2 treatment stimulated expression of mexEF-oprN while R-6 treatment led to increased mexAB-oprM expression. Further expansion into a small library of virulence inhibitors revealed chemical motifs that trigger increases in RND efflux pump expression. Additionally, activation of these efflux pumps suggests low accumulation of virulence inhibitors in WT PA14. Treatment of an efflux pump-deficient strain with R-2 or R-6 resulted in inhibition of several virulence factors, for example R-2 was found to abolish swimming motility. Collectively, treatment with either R-2 or R-6 gives rise to a convoluted transcriptomic response, confounded by the impact of efflux pump expression on the system. However, understanding the moieties that lead to high expression of the efflux pumps enables further rational design of novel virulence inhibitors that do not cause RND efflux pump activation.
2025-08-13 | GSE291940 | GEO
Project description:A first line of defense against pathogen infections is the recognition of pathogen-associated molecular patterns (PAMPs), leading to PAMP-triggered immunity (PTI). MicroRNAs (miRNAs) are primarily known as central regulators of plant development, but a few have also been connected to immunity. We have found that several fungal pathogens lead to a reduction in miR396 levels, suggesting that miR396 are negative regulators of downstream defense responses. In agreement with such as scenario, constitutive attenuation of miR396 activity enhances resistance to infection by fungal pathogens, while increased miR396 activity reduces pathogen resistance. We conclude that constitutive reduction of miR396 levels confer a primed state for enhanced defense reactions
2017-02-28 | GSE76819 | GEO
Project description:Pneumocystis is a relevant genetic system to study centromere formation in relation with host adaptation. How centromeres are formed and maintained in strongly host adapted fungal pathogens is poorly investigated. Centromeres are genomic regions that coordinate accurate chromosomal segregation during mitosis and meiosis. Yet, despite their essential function, centromeres evolve rapidly across eukaryotes. CENP-A, a variant of histone H3 is the epigenetic marker that define centromeres in most eukaryotes. Centromeres are often the sites of chromosomal breaks which contribute to genome shuffling and promote speciation by inhibiting gene flow. Genome shuffling allows genome reconfiguration suitable for survival in new environment such as pathogen adaptation to new hosts. Here, we study the evolution of centromeres in closely related species of mammalian specific pathogens of the fungal phylum of Ascomycota. Long term culture of Pneumocystis species is currently untenable. Using heterologous complementation, we show that Pneumocystis CENP-A ortholog is functionally equivalent to fission yeast Cnp1. Using a short-term in vitro culture, infected animal models and ChIP-seq, we identified centromeres in three Pneumocystis species that diverged ~100 Mya ago. Each species has 17 unique short regional centromeres (< 10kb) in 17 monocentric chromosomes. The centromeres are flanked by heterochromatin. They span active genes, lack conserved DNA sequence motifs, and repeats.These features suggest an epigenetic specification of centromere function.
2025-05-31 | GSE232475 | GEO
Project description:Efflux pumps of the resistance-nodulation-division (RND) superfamily, particularly the AcrAB-TolC and MexAB-OprM, besides mediating intrinsic and acquired resistance, also intervene in bacterial pathogenicity. Inhibitors of such pumps could restore activities of antibiotics and curb bacterial virulence. Here, we identify pyrrole-based compounds that boost antibiotic activity in Escherichia coli and Pseudomonas aeruginosa by inhibiting their archetype RND transporters. The discovered efflux pump inhibitors (EPIs) inhibit the efflux of fluorescent probes, attenuate persister formation, and diminish resistant mutant development. Molecular docking and biophysical studies revealed that the EPIs bind to AcrB. EPIs also possess an anti-pathogenic potential and attenuate P. aeruginosa virulence in vivo. The excellent efficacy of the EPI-antibiotic combination was evidenced in animal lung infection and sepsis protection models. These findings indicate that EPIs discovered herein with no off-target effects and negligible toxicity are potential antibiotic adjuvants to address life-threatening bacterial infections.
2024-03-18 | GSE210309 | GEO
Project description:The study examines transcriptomes of Trifolium pratense (red clover) roots challenged with the fungal pathogens Fusarium oxysporum and Phoma medicaginis. Fungal infection broadly activated both core metabolic processes and specialized metabolic pathways, including transcripts encoding phenylpropanoid and (iso)flavonoid biosynthetic enzymes. Among 33 predicted isoflavonoid-pathway genes, many were differentially expressed in at least one fungal treatment, with the late steps of pterocarpan biosynthesis particularly induced by P. medicaginis. These comparative transcriptomes provide insight into the activation and regulation of biotic stress responses as well as the engagement of legume-specific isoflavonoid biosynthesis, a pathway closely linked to antimicrobial defense.
2026-06-10 | GSE310497 | GEO
Project description:Calcineurin-nuclear factor of activated T-cell (CN-NFAT) inhibitors are widely clinically used drugs for immunosuppression but besides their required T-cell response inhibition, they also undesirably affect innate immune cells. Disruption of innate immune cell function can explain the observed susceptibility of CN-NFAT inhibitors-treated patients to opportunistic fungal infections. Neutrophils play a crucial role in the innate immunity pathogen defense, while however the effect of CN-NFAT inhibitors on neutrophil function is poorly described. Thus, we tested the response of human neutrophils to fungal pathogens, namely Candida albicans and Aspergillus fumigatus in the presence of CN-NFAT inhibitors. We report that the NFAT pathway members are expressed in neutrophils and mediates part of the neutrophil response to pathogens. Upon pathogen exposure, neutrophils underwent profound transcriptomic changes. Importantly, genes involved in the regulation of the immune response and chemotaxis, including the chemokines CCL2 , CCL3, and CCL4 were significantly upregulated. The presence of CN-NFAT inhibitors attenuated the expression of these chemokines and impaired the ability of neutrophils to chemoattract other immune cells. Our results amend knowledge about the impact of CN-NFAT inhibition in human neutrophils.
2024-05-21 | GSE259282 | GEO
Project description:To assess the contribution to defenses against necrotrophic fungal pathogens that may be mediated by recognition of oligogalacturonides (OGs), cell wall fragments released by the activity of fungal polygalacturonases, we treated seedlings with OGs and assayed transcript levels 1 and 6 hours after addition of OGs to culture medium. For each sample, approximately 30 seedlings were grown in shallow liquid MS medium for 10 days. Plants were then treated with either 200 ug/ml OGs or, for control plants, an equal volume of water. Three replicate samples were assayed for each treatment.
2007-04-19 | E-NASC-76 | biostudies-arrayexpress