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Unexpected Cell Wall Alteration-Mediated Bactericidal Activity of the Antifungal Caspofungin against Vancomycin-Resistant Enterococcus faecium
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).ORCID-id: 0000-0002-8349-360x
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2020 (Engelska)Ingår i: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 64, nr 10, artikel-id e01261-20Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Enterococcus faecium has become a major opportunistic pathogen with the emergence of vancomycin-resistant enterococci (VRE). As part of the gut microbiota, they have to cope with numerous stresses, including effects of antibiotics and other xenobiotics, especially in patients hospitalized in intensive care units (ICUs) who receive many medications. The aim of this study was to investigate the impact of the most frequently prescribed xenobiotics for ICU patients on fitness, pathogenicity, and antimicrobial resistance of the vanB-positive E. faecium Aus0004 reference strain. Several phenotypic analyses were carried out, and we observed that caspofungin, an antifungal agent belonging to the family of echinocandins, had an important effect on E. faecium growth in vitro. We confirmed this effect by electron microscopy and peptidoglycan analysis and showed that, even at a subinhibitory concentration (1/4x MIC, 8 mg/liter), caspofungin had an impact on cell wall organization, especially with respect to the abundance of some muropeptide precursors. By transcriptome sequencing (RNA-seq), it was also shown that around 20% of the transcriptome was altered in the presence of caspofungin, with 321 and 259 significantly upregulated and downregulated genes, respectively. Since the fungal target of caspofungin (i.e., beta-1,3-glucan synthase) was absent in bacteria, the mechanistic pathway of caspofungin activity was investigated. The repression of genes involved in the metabolism of pyruvate seemed to have a drastic impact on bacterial cell viability, while a decrease of glycerol metabolism could explain the conformational modifications of peptidoglycan. This is the first report of caspofungin antibacterial activity against E. faecium, highlighting the potential impact of nonantibiotic xenobiotics against bacterial pathogens.

Ort, förlag, år, upplaga, sidor
AMER SOC MICROBIOLOGY , 2020. Vol. 64, nr 10, artikel-id e01261-20
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Farmaceutiska vetenskaper
Identifikatorer
URN: urn:nbn:se:umu:diva-176185DOI: 10.1128/AAC.01261-20ISI: 000574990600012PubMedID: 32778553Scopus ID: 2-s2.0-85091469671OAI: oai:DiVA.org:umu-176185DiVA, id: diva2:1479293
Tillgänglig från: 2020-10-26 Skapad: 2020-10-26 Senast uppdaterad: 2023-03-24Bibliografiskt granskad

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Hernandez, Sara B.Cava, Felipe

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Hernandez, Sara B.Gravey, FrancoisCava, Felipe
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Institutionen för molekylärbiologi (Medicinska fakulteten)Molekylär Infektionsmedicin, Sverige (MIMS)
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Antimicrobial Agents and Chemotherapy
Farmaceutiska vetenskaper

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