Synergistic activity of caspofungin and posaconazole against Candida auris biofilms based on phenotypic, transcriptomic and in vivo insights
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PROVIDER: PRJNA1290291 | ENA |
REPOSITORIES: ENA
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Project description:The World Health Organization (WHO) had designated Candida auris as a critical public health threat due to its multidrug resistance to antifungal agents, high mortality rate, and its ability to cause nosocomial outbreaks. A matter of serious concern is that conventional antifungal monotherapies is frequently ineffective against biofilm-associated C. auris infection, highlighting the need for more effective strategies. Combination therapies have demonstrated improved efficacy and specificity, and may also slow the development of antifungal resistance. Therefore, this study aimed to evaluate the in vitro and in vivo efficacy of caspofungin (CAS) and posaconazole (POSA) in combination against sessile C. auris isolates from the South Asian clade and to characterize the associated transcriptomic responses. The CAS with POSA combination resulted in a significant reduction in median minimum inhibitory concentrations (4–32-fold for CAS and 8–64-fold for POSA) compared to monotherapies. Synergistic interactions were observed in all isolates tested, with fractional inhibitory concentration indices ranging from 0.078 to 0.31. In line with the in vitro findings, synergistic interactions were confirmed by in vivo experiments. The fungal kidney burden decreases were three log volumes in mice treated with combination of 1 mg/kg/day caspofungin and 1.5 mg/kg/day posaconazole. To investigate the gene expression changes in response to combination treatment, 612 genes showed increased expression and 465 genes were downregulated relative to the untreated control biofilms (fold change >1.5 or <–1.5). Notably, genes involved in biofilm dispersion, oxidative stress response, iron metabolism, and glycolysis were downregulated, whereas those associated with cell wall organization or biogenesis, osmotic stress response, calcium signaling, drug efflux, biofilm formation, and the biosynthesis of ergosterol and chitin were upregulated. These findings demonstrate the potent synergistic activity of CAS and POSA against C. auris biofilms and provide insight into C. auris antifungal therapeutic responses, thereby contributing to the development of more effective antifungal treatment strategies.
2025-09-01 | GSE302377 | GEO
Project description:Candida auris clade III isolate B12039 was spread on YPD plate supplemented with 250 ng/ml, 500 ng/ml, 1000 ng/ml, and 2000 ng/ml of caspofungin. In total, 33 adaptors were chosen for further analysis. We did sequencing of them as as well as the parent. 9 adaptors (250-1 - 250-9) were obtained from YPD+250ng/ml caspofugin. 6 adaptors (500-1 - 500-6) were obtained from YPD+250ng/ml caspofugin. 6 adaptors (1000-1 - 1000-6) were obtained from YPD+250ng/ml caspofugin. 12 adaptors (2000-1 - 2000-12) were obtained from YPD+250ng/ml caspofugin
2021-07-23 | E-MTAB-10627 | biostudies-arrayexpress
Project description:Candida auris is frequently associated with biofilm-related invasive infections. The resistant profile of these biofilms necessitates innovative therapeutic options, where quorum sensing may be a potential target. Farnesol and tyrosol are two fungal quorum-sensing molecules with antifungal effects at supraphysiological concentrations. Here, we performed genome-wide transcript profiling with C. auris biofilms following farnesol or tyrosol exposure using transcriptome sequencing (RNA-Seq). Since transition metals play a central role in fungal virulence and biofilm formation, levels of intracellular calcium, magnesium, and iron were determined following farnesol or tyrosol treatment using inductively coupled plasma optical emission spectrometry. Farnesol caused an 89.9% and 73.8% significant reduction in the calcium and magnesium content, respectively, whereas tyrosol resulted in 82.6%, 76.6%, and 81.2% decrease in the calcium, magnesium, and iron content, respectively, compared to the control. Genes involved in biofilm events, glycolysis, ergosterol biosynthesis, fatty acid oxidation, iron metabolism, and autophagy were primarily affected in treated cells. To prove ergosterol quorum-sensing molecule interactions, microdilution-based susceptibility testing was performed, where the complexation of farnesol, but not tyrosol, with ergosterol was impeded in the presence of exogenous ergosterol, resulting in a minimum inhibitory concentration increase in the quorum-sensing molecules. This study revealed several farnesol- and tyrosol-specific responses, which will contribute to the development of alternative therapies against C. auris biofilms.
2023-12-11 | GSE233427 | GEO
Project description:Combination therapies can be a promising tool to augment the antifungal activity of azole drugs against resistant Candida species. Here, we report the interaction between aprepitant, an antiemetic agent, and azole drugs against different Candida species including the emerging multidrug-resistant C. auris. Particularly, aprepitant enhanced the antifungal activity of itraconazole against C. auris by reducing its minimum inhibitory concentration (MIC) by 2-8 folds. Using Caenorhabditis elegans as an in vivo infection model, the aprepitant/itraconazole combination significantly prolonged the survival of the infected nematodes by ~90% and reduced the fungal burden by ~92% relative to the untreated control. Interestingly, the aprepitant/itraconazole combination exerted a potent fungicidal activity against both planktonic and adherent C. auris biofilms. Further, aprepitant/itraconazole displayed broad-spectrum synergistic interactions against other medically important Candida species including C. albicans, C. krusie, C. tropicalis, and C. parapsilosis (ƩFICI ranged from 0.08 to 031). Comparative transcriptomic profiling indicated aprepitant/itraconazole interferes significantly with metal ions homeostasis and compromises the ROS (reactive oxygen species) detoxification ability of C. auris. This study presents aprepitant as a novel, potent and broad-spectrum azole chemosensitizing agent that warrants further investigation.
2020-10-19 | GSE148749 | GEO
Project description:This project investigated the signature profiles of C. albicans planktonic cells and biofilms in response to caspofungin.
2021-01-08 | PXD023480 |
Project description:Synergistic interactions in mixed biofilms
| PRJEB43664 | ENA
Project description:Whole genome sequencing of caspofungin adaptors in Candida auris
| PRJEB45903 | ENA
Project description:In this study, we designed a novel antifungal agent, PQA-Az-13 that demonstrated antifungal activity against C. auris biofilms. Cellular proteomics indicated that PQA-Az-13 partially or completely inhibited numerous enzymatic proteins in C. auris biofilms, particularly those involved in both amino acid biosynthesis and metabolism processes, as well as in general energy-producing processes. Due to its hydrophobic nature and limited aqueous solubility, PQA-Az-13 was encapsulated in cationic liposomes and characterized by biophysical and spectral techniques. PQA-Az-13 liposomes demonstrated enhanced antifungal activity levels against both C. auris in in vitro biofilms and ex vivo skin colonization models.
2023-12-07 | PXD046911 | Pride
Project description:The limited number of antifungals and the emergence of multidrug-resistant Candida auris pose a significant challenge to human medicine. Here, we utilized combinatorial drug therapy as an approach to augment the activity of current azole antifungals against C. auris. We evaluated the fluconazole chemosensitization activity of 1547 FDA-approved drugs and clinical molecules against an azole-resistant strain of C. auris. This led to the discovery that lopinavir, an antiviral drug, is a potent agent capable of sensitizing C. auris to the effect of azole antifungals. At a therapeutically achievable concentration (4-8 µg/ml), lopinavir exhibited potent synergistic interactions with azole drugs, particularly with itraconazole, against C. auris (ΣFICI ranged from 0.05-0.50). The lopinavir/itraconazole combination enhanced the survival rate of C. auris-infected Caenorhabditis elegans by 90% and reduced the fungal burden in infected nematodes by 88.5% (p < 0.05). Moreover, lopinavir enhanced the antifungal activity of itraconazole against other medically important Candida species including C. albicans, C. tropicalis, C. glabrata, C. tropicalis, and C. parapsilosis. Comparative transcriptomic profiling revealed that lopinavir interferes with glucose permeation and ATP synthesis. This compromises the function of the efflux pumps presents in C. auris enhancing sensitivity to azole antifungals, as demonstrated by Nile red efflux assays. This study presents lopinavir as a novel, potent and broad-spectrum azole chemosensitizing agent that warrants further investigation against recalcitrant Candida infections.
2020-10-06 | GSE148341 | GEO
Project description:30h of growth biofilms in microfermentors were exposed to caspofungin 0.5 µg/ml, caspofungin 5 µg/ml, fluconazole 80 µg/ml or amphotericin B 8 µg/ml. Control and antifungal-exposed biofilms were recovered at t= 0, 30, 60 and 120 min post exposure to antifungal.
2010-03-02 | E-MEXP-2436 | biostudies-arrayexpress