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A highly substituted ring-fused 2-pyridone compound targeting PrfA and the efflux regulator BrtA in listeria monocytogenes
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). QureTech Bio, Umeå, Sweden. (Johansson)ORCID iD: 0000-0002-2259-6883
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).ORCID iD: 0000-0003-1803-2708
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
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2023 (English)In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 14, no 3, article id e0044923Article in journal, Letter (Refereed) Published
Abstract [en]

Listeria monocytogenes is a facultative Gram-positive bacterium that causes listeriosis, a severe foodborne disease. We previously discovered that ring-fused 2-pyridone compounds can decrease virulence factor expression in Listeria by binding and inactivating the PrfA virulence activator. In this study, we tested PS900, a highly substituted 2-pyridone that was recently discovered to be bactericidal to other Gram-positive pathogenic bacteria, such as Staphylococcus aureus and Enterococcus faecalis. We show that PS900 can interact with PrfA and reduce the expression of virulence factors. Unlike previous ring-fused 2-pyridones shown to inactivate PrfA, PS900 had an additional antibacterial activity and was found to potentiate sensitivity toward cholic acid. Two PS900-tolerant mutants able to grow in the presence of PS900 carried mutations in the brtA gene, encoding the BrtA repressor. In wild-type (WT) bacteria, cholic acid binds and inactivates BrtA, thereby alleviating the expression of the multidrug transporter MdrT. Interestingly, we found that PS900 also binds to BrtA and that this interaction causes BrtA to dissociate from its binding site in front of the mdrT gene. In addition, we observed that PS900 potentiated the effect of different osmolytes. We suggest that the increased potency of cholic acid and osmolytes to kill bacteria in the presence of PS900 is due to the ability of the latter to inhibit general efflux, through a yet-unknown mechanism. Our data indicate that thiazolino 2-pyridones constitute an attractive scaffold when designing new types of antibacterial agents.

IMPORTANCE: Bacteria resistant to one or several antibiotics are a very large problem, threatening not only treatment of infections but also surgery and cancer treatments. Thus, new types of antibacterial drugs are desperately needed. In this work, we show that a new generation of substituted ring-fused 2-pyridones not only inhibit Listeria monocytogenes virulence gene expression, presumably by inactivating the PrfA virulence regulator, but also potentiate the bactericidal effects of cholic acid and different osmolytes. We identified a multidrug repressor as a second target of 2-pyridones. The repressor–2-pyridone interaction displaces the repressor from DNA, thus increasing the expression of a multidrug transporter. In addition, our data suggest that the new class of ring-fused 2-pyridones are efficient efflux inhibitors, possibly explaining why the simultaneous addition of 2-pyridones together with cholic acid or osmolytes is detrimental for the bacterium. This work proves conclusively that 2-pyridones constitute a promising scaffold to build on for future antibacterial drug design.

Place, publisher, year, edition, pages
American Society for Microbiology, 2023. Vol. 14, no 3, article id e0044923
Keywords [en]
2-pyridones, BrtA, Listeria monocytogenes, PrfA, antibacterial, antibiotic
National Category
Biochemistry and Molecular Biology Microbiology in the medical area Organic Chemistry
Research subject
molecular cell biology
Identifiers
URN: urn:nbn:se:umu:diva-214132DOI: 10.1128/mbio.00449-23ISI: 000975886700001PubMedID: 37120759Scopus ID: 2-s2.0-85172894238OAI: oai:DiVA.org:umu-214132DiVA, id: diva2:1794445
Funder
Familjen Erling-Perssons StiftelseNIH (National Institutes of Health), RO1AI134847-01A1NIH (National Institutes of Health), 1IU19AI157797-01Olle Engkvists stiftelseVinnova, 2019-05491Swedish Research Council, 2020-02005Swedish Research Council, 2018-04589Swedish Research Council, 202105040JAvailable from: 2023-09-05 Created: 2023-09-05 Last updated: 2023-10-13Bibliographically approved

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Tükenmez, HasanSingh, PardeepSarkar, SouvikLindgren, CeciliaVaitkevicius, KarolisBonde, MariSauer-Eriksson, A. ElisabethAlmqvist, FredrikJohansson, Jörgen

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Tükenmez, HasanSingh, PardeepSarkar, SouvikLindgren, CeciliaVaitkevicius, KarolisBonde, MariSauer-Eriksson, A. ElisabethAlmqvist, FredrikJohansson, Jörgen
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Department of Molecular Biology (Faculty of Medicine)Department of ChemistryUmeå Centre for Microbial Research (UCMR)Molecular Infection Medicine Sweden (MIMS)
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Biochemistry and Molecular BiologyMicrobiology in the medical areaOrganic Chemistry

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