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dc.contributor.authorSingleton, Amanda Holstad
dc.contributor.authorBergum, Olaug Elisabeth Torheim
dc.contributor.authorSøgaard, Caroline Krogh
dc.contributor.authorRøst, Lisa M.
dc.contributor.authorOlsen, Cecilie Elisabeth
dc.contributor.authorBlindheim, Fredrik Heen
dc.contributor.authorRæder, Synnøve Brandt
dc.contributor.authorBjørnstad, Frithjof Andreas
dc.contributor.authorSundby, Eirik
dc.contributor.authorHoff, Bård Helge
dc.contributor.authorBruheim, Per
dc.contributor.authorOtterlei, Marit
dc.date.accessioned2024-02-12T13:11:17Z
dc.date.available2024-02-12T13:11:17Z
dc.date.created2023-10-27T14:40:06Z
dc.date.issued2023
dc.identifier.citationFrontiers in Microbiology. 2023, 14 .en_US
dc.identifier.issn1664-302X
dc.identifier.urihttps://hdl.handle.net/11250/3117018
dc.description.abstractThe past few decades have been plagued by an increasing number of infections caused by antibiotic resistant bacteria. To mitigate the rise in untreatable infections, we need new antibiotics with novel targets and drug combinations that reduce resistance development. The novel β-clamp targeting antimicrobial peptide BTP-001 was recently shown to have a strong additive effect in combination with the halogenated pyrrolopyrimidine JK-274. In this study, the molecular basis for this effect was examined by a comprehensive proteomic and metabolomic study of the individual and combined effects on Staphylococcus aureus. We found that JK-274 reduced activation of several TCA cycle enzymes, likely via increasing the cellular nitric oxide stress, and BTP-001 induced oxidative stress in addition to inhibiting replication, translation, and DNA repair processes. Analysis indicated that several proteins linked to stress were only activated in the combination and not in the single treatments. These results suggest that the strong additive effect is due to the activation of multiple stress responses that can only be triggered by the combined effect of the individual mechanisms. Importantly, the combination dose required to eradicate S. aureus was well tolerated and did not affect cell viability of immortalized human keratinocyte cells, suggesting a species-specific response. Our findings demonstrate the potential of JK-274 and BTP-001 as antibiotic drug candidates and warrant further studies.en_US
dc.language.isoengen_US
dc.publisherFrontiers Mediaen_US
dc.rightsNavngivelse 4.0 Internasjonal*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/deed.no*
dc.titleActivation of multiple stress responses in Staphylococcus aureus substantially lowers the minimal inhibitory concentration when combining two novel antibiotic drug candidatesen_US
dc.title.alternativeActivation of multiple stress responses in Staphylococcus aureus substantially lowers the minimal inhibitory concentration when combining two novel antibiotic drug candidatesen_US
dc.typePeer revieweden_US
dc.typeJournal articleen_US
dc.description.versionpublishedVersionen_US
dc.source.pagenumber0en_US
dc.source.volume14en_US
dc.source.journalFrontiers in Microbiologyen_US
dc.identifier.doi10.3389/fmicb.2023.1260120
dc.identifier.cristin2189340
cristin.ispublishedtrue
cristin.fulltextoriginal
cristin.qualitycode2


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