Milbemycins: more than efflux inhibitors for fungal pathogens
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ABSTRACT:
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:Existing antifungal agents are still confronted to activities limited to specific fungal species and to the development of resistance. Several improvements are possible either by tackling and overcoming resistance or exacerbating the activity of existing antifungal agents. In Candida glabrata, azole resistance is almost exclusively mediated by ABC transporters (including C. glabrata CDR1 [CgCDR1] and CgCDR2) via gain-of-function mutations in the transcriptional activator CgPDR1 or by mitochondrial dysfunctions. We also observed that azole resistance was correlating with increasing virulence and fitness of C. glabrata in animal models of infection. This observation motivated the re-exploitation of ABC transporter inhibitors as a possible therapeutic intervention to decrease not only the development of azole resistance but also to interfere with the virulence of C. glabrata. Milbemycins are known ABC transporter inhibitors, and here we used commercially available milbemycin A3/A4 oxim derivatives to verify this effect. As expected, the derivatives were inhibiting C. glabrata efflux with the highest activity for A3 oxim below 1 ?g/ml. More surprising was that oxim derivatives had intrinsic fungicidal activity above 3.2 ?g/ml, thus highlighting effects additional to the efflux inhibition. Similar values were obtained with C. albicans. Our data show that the fungicidal activity could be related to reactive oxygen species formation in these species. Transcriptional analysis performed both in C. glabrata and C. albicans exposed to A3 oxim highlighted a core of commonly regulated genes involved in stress responses, including genes involved in oxidoreductive processes, protein ubiquitination, and vesicle trafficking, as well as mitogen-activated protein kinases. However, the transcript profiles contained also species-specific signatures. Following these observations, experimental treatments of invasive infections were performed in mice treated with the commercial A3/A4 oxim preparation alone or in combination with fluconazole. Tissue burden analysis revealed that oxims on their own were able to decrease fungal burdens in both Candida species. In azole-resistant isolates, oxims acted synergistically in vivo with fluconazole to reduce fungal burden to levels of azole-susceptible isolates. In conclusion, we show here the potential of milbemycins not only as drug efflux inhibitors but also as effective fungal growth inhibitors in C. glabrata and C. albicans.
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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: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: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
Project description:Fungal pathogens cause deadly diseases in living organisms. Numerous studies suggest that lysine acetylation is a critical regulator in pathogenic fungi, but an in-depth and cross-species analysis of the acetylome in major pathogenic fungi is lacking, and our knowledge of the mechanism of acetylation in manipulating fungal pathogenicity is limited. Here, we show that lysine acetylation plays essential roles during cryptococcosis through modulating the gene expression of important virulence factors and the activity of key players in important pathways. We show that the Cryptococcus TOR pathway and translational elongation process are functionally regulated by acetylation via the HDAC and sirtuin families, respectively. Through comparative acetylome network analysis among pathogens and baker’s yeast, we demonstrate significant correlation between acetylation sites and virulence factors, indicating a unique selective pressure on lysine acetylation motifs in pathogenic fungi. These results provide a basis for understanding the regulation of fungal pathogenicity by posttranslational lysine acetylation.
2019-04-29 | PXD010354 | Pride
Project description:Herein we i) identify Coccidioides spp.-specific CAZymes by bioinformatically comparing the CAZyme repertoire (CAZome) of Coccidioides spp. to other common fungal lung pathogens and a non-pathogenic close fungal relative, ii) experimentally evaluate Coccidioides spp. CAZyme abundance in vivo and in vitro, and iii) identify Coccidioides genus-specific N-glycans by experimentally determining the N-glycan population (N-glycome) of Coccidioides-infected lung tissues using tandem mass spectrometry. As far as we are aware, this is the first use of mass spectrometry to compare the N-glycomes and CAZomes of different fungal genera during infection in human hosts.
2019-11-11 | PXD012459 | Pride