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Ring-fused 2-pyridones effective against multidrug-resistant Gram-positive pathogens and synergistic with standard-of-care antibiotics

Nye, Taylor M. (author)
Department of Molecular Microbiology, Center for Women’s Infectious Disease Research, Washington University, School of Medicine, MO, St. Louis, United States
Tükenmez, Hasan, 1987- (author)
Umeå universitet,Kemiska institutionen,Umeå Centre for Microbial Research (UCMR),Institutionen för molekylärbiologi (Medicinska fakulteten)
Singh, Pardeep (author)
Umeå universitet,Kemiska institutionen,Umeå Centre for Microbial Research (UCMR)
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Flores-Mireles, Ana L. (author)
Department of Biological Sciences, University of Notre Dame, Notre Dame, India
Obernuefemann, Chloe L.P. (author)
Department of Molecular Microbiology, Center for Women’s Infectious Disease Research, Washington University, School of Medicine, MO, St. Louis, United States
Pinkner, Jerome S. (author)
Department of Molecular Microbiology, Center for Women’s Infectious Disease Research, Washington University, School of Medicine, MO, St. Louis, United States
Sarkar, Souvik (author)
Umeå universitet,Kemiska institutionen,Umeå Centre for Microbial Research (UCMR)
Bonde, Mari (author)
Umeå universitet,Kemiska institutionen,Institutionen för molekylärbiologi (Medicinska fakulteten)
Lindgren, Anders E. G. (author)
Umeå universitet,Kemiska institutionen,Umeå Centre for Microbial Research (UCMR)
Dodson, Karen W. (author)
Department of Molecular Microbiology, Center for Women’s Infectious Disease Research, Washington University, School of Medicine, MO, St. Louis, United States
Johansson, Jörgen (author)
Umeå universitet,Umeå Centre for Microbial Research (UCMR),Institutionen för molekylärbiologi (Medicinska fakulteten)
Almqvist, Fredrik (author)
Umeå universitet,Kemiska institutionen,Umeå Centre for Microbial Research (UCMR)
Caparon, Michael G. (author)
Department of Molecular Microbiology, Center for Women’s Infectious Disease Research, Washington University, School of Medicine, MO, St. Louis, United States
Hultgren, Scott J. (author)
Department of Molecular Microbiology, Center for Women’s Infectious Disease Research, Washington University, School of Medicine, MO, St. Louis, United States
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Department of Molecular Microbiology, Center for Women’s Infectious Disease Research, Washington University, School of Medicine, MO, St Louis, United States Kemiska institutionen (creator_code:org_t)
2022-10-17
2022
English.
In: Proceedings of the National Academy of Sciences of the United States of America. - : PNAS. - 0027-8424 .- 1091-6490. ; 119:43
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https://doi.org/10.1...
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https://umu.diva-por... (primary) (Raw object)
https://urn.kb.se/re...
https://doi.org/10.1...
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Mikrobiologi inom det medicinska området (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Microbiology in the medical area (hsv//eng)

Keyword

antibiotic resistance
antibiotic synergy
multidrug-resistant pathogens
VRE

Publication and Content Type

ref (subject category)
art (subject category)

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