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Ring-fused 2-pyridones effective against multidrug-resistant Gram-positive pathogens and synergistic with standard-of-care antibiotics
Department of Molecular Microbiology, Center for Women’s Infectious Disease Research, Washington University, School of Medicine, MO, St. Louis, United States.
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, 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).
Department of Biological Sciences, University of Notre Dame, Notre Dame, India.
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2022 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 119, no 43, article id e2210912119Article in journal (Refereed) Published
Abstract [en]

The alarming rise of multidrug-resistant Gram-positive bacteria has precipitated a healthcare crisis, necessitating the development of new antimicrobial therapies. Here we describe a new class of antibiotics based on a ring-fused 2-pyridone backbone, which are active against vancomycin-resistant enterococci (VRE), a serious threat as classified by the Centers for Disease Control and Prevention, and other multidrug-resistant Gram-positive bacteria. Ring-fused 2-pyridone antibiotics have bacteriostatic activity against actively dividing exponential phase enterococcal cells and bactericidal activity against nondividing stationary phase enterococcal cells. The molecular mechanism of drug-induced killing of stationary phase cells mimics aspects of fratricide observed in enterococcal biofilms, where both are mediated by the Atn autolysin and the GelE protease. In addition, combinations of sublethal concentrations of ring-fused 2-pyridones and standard-of-care antibiotics, such as vancomycin, were found to synergize to kill clinical strains of VRE. Furthermore, a broad range of antibiotic resistant Gram-positive pathogens, including those responsible for the increasing incidence of antibiotic resistant healthcare-associated infections, are susceptible to this new class of 2-pyridone antibiotics. Given the broad antibacterial activities of ring-fused 2-pyridone compounds against Gram-positive (GmP) bacteria we term these compounds GmPcides, which hold promise in combating the rising tide of antibiotic resistant Gram-positive pathogens.

Place, publisher, year, edition, pages
PNAS , 2022. Vol. 119, no 43, article id e2210912119
Keywords [en]
antibiotic resistance, antibiotic synergy, multidrug-resistant pathogens, VRE
National Category
Microbiology in the medical area
Identifiers
URN: urn:nbn:se:umu:diva-201191DOI: 10.1073/pnas.2210912119PubMedID: 36252016Scopus ID: 2-s2.0-85141283133OAI: oai:DiVA.org:umu-201191DiVA, id: diva2:1724104
Funder
NIH (National Institutes of Health), 1U19AI157797-01NIH (National Institutes of Health), R01AI134847-01A1NIH (National Institutes of Health), R01DK128805NIH (National Institutes of Health), RO1DK51406NIH (National Institutes of Health), T32AI007172Swedish Research Council, 2018-04589Swedish Research Council, 2021-05040JThe Kempe Foundations, SMK-1755Available from: 2023-01-05 Created: 2023-01-05 Last updated: 2023-08-25Bibliographically approved

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Tükenmez, HasanSingh, PardeepSarkar, SouvikBonde, MariLindgren, Anders E. G.Johansson, JörgenAlmqvist, Fredrik

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Tükenmez, HasanSingh, PardeepSarkar, SouvikBonde, MariLindgren, Anders E. G.Johansson, JörgenAlmqvist, Fredrik
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Department of ChemistryUmeå Centre for Microbial Research (UCMR)Department of Molecular Biology (Faculty of Medicine)
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