Investigating the mechanism by which the natural product compound puupehenone potentiates the antifungal drug caspofungin
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ABSTRACT:
PROVIDER: PRJNA590180 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10486113_1.fastq.gz | Fastqsanger.gz | |||
| SRR10486113_2.fastq.gz | Fastqsanger.gz | |||
| SRR10486114_1.fastq.gz | Fastqsanger.gz | |||
| SRR10486114_2.fastq.gz | Fastqsanger.gz | |||
| SRR10486115_1.fastq.gz | Fastqsanger.gz |
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Project description:Enterococcus faecium has become a major opportunistic pathogen with the emergence of multidrug-resistant clones that are well-adapted to the hospital environment. As part of the vast diversity of gut microbiota, they are faced with different environmental stress, including antimicrobial pressure. By contrast, little is known about the effect of non-antibiotic molecules on bacterial physiology while numerous drugs are used in inpatients, especially those hospitalized in intensive care units (ICUs). The aim of this study was to investigate the impact of the most prescribed xenobiotics in ICUs on fitness, pathogenicity and antimicrobial resistance of E. faecium. Several phenotypic analysis was carried out and we rapidly brought to light that caspofungin, an antifungal agent belonging to the echinocandin family, seemed to have an important impact on E. faecium growth. Since the fungal target of caspofungin [beta-(1,3)-glucan synthase] is absent in enterococci, the mechanism of caspofungin action was investigated by several approaches. First, we decided to confirm this result by electronic microscopy and a peptidoglycan analysis by Ultra Performance Liquid Chromatography coupled with mass spectrometry (UPLC-MS/MS). Again, we highlighted that caspofungin even at subinhibitory concentrations (SICs) seemed to have an impact on cell wall organization especially in muropeptide precursors abundance. Then, a transcriptomic analysis was performed by RNA-seq (HiSeq 2500, Illumina) using the vanB-positive reference strain E. faecium Aus0004 in the presence or absence of caspofungin SIC (8 mg/L i.e., ¼ of the MIC). Transcriptomic analysis showed that the expression of 568 genes (19.9% of the genome) was significantly altered in the presence of caspofungin SIC, with 323 genes induced (fold change >2, p-value <0.1) and 245 genes repressed (fold change <-2, p-value <0.1). Regarding the repressed genes, the pdhABCD operon is largely downregulated (fold changes -4.3, -9.7, -6.9 and -6.4, respectively). This operon encoded components of the pyruvate deshydrogenase multienzyme complex involved in bacterial energetic pathway by the citrate cycle (i.e., TCA cycle). Moreover, it seemed that the glycerol metabolism pathway and in particular the glpOKF operon is downregulated too. The dramatic alteration of TCA seemed to have an drastic impact on bacterial cells viability indeed decrease of glycerol metabolism could explain the conformational modifications of peptidoglycan.
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Project description:The identification of novel transcription factors associated to antifungal response may allow the discovery of fungal specific targets for new therapeutic strategies. A collection of 241 C. albicans transcriptional regulators mutants was screened for altered susceptibility to fluconazole, caspofungin, amphotericin B, and 5-fluorocytosine. Thirteen of these mutants not yet identified in their role in antifungal response were further investigated, and the function of one of them, mutant for orf19.6102 (RCA1) was characterized by transcriptome analysis. Strand specific RNA sequencing and phenotypic tests assigned Rca1 as the regulator of hyphal formation through the cAMP/PKA signaling pathway and the transcription factor Efg1, but also probably through its interaction with a transcriptional repressor, most likely Tup1. The mechanisms responsible for the high level of resistance to caspofungin and fluconazole observed resulting from Rca1 deletion were investigated. From our observations, we propose that caspofungin resistance was the consequence of the deregulation of cell wall gene expression, and that fluconazole resistance was linked to the modulation of the cAMP/PKA signaling pathway activity. In conclusion, our large-scale screening of a C. albicans transcription factor mutants collection allowed the identification of new effectors of the response to antifungals. The functional characterization of Rca1 assigned this TF and its downstream targets as promising candidates for the development of new therapeutic strategies, as Rca1 influences host sensing, hyphal development, and antifungal response.
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