Ring-fused 2-pyridones effective against multidrug-resistant Gram-positive pathogens and synergistic with standard-of-care antibiotics
| Autor: | Taylor M. Nye, Hasan Tükenmez, Pardeep Singh, Ana L. Flores-Mireles, Chloe L. P. Obernuefemann, Jerome S. Pinkner, Souvik Sarkar, Mari Bonde, Anders E. G. Lindgren, Karen W. Dodson, Jörgen Johansson, Fredrik Almqvist, Michael G. Caparon, Scott J. Hultgren |
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| Rok vydání: | 2022 |
| Předmět: |
antibiotic resistance
Multidisciplinary Pyridones VRE Microbial Sensitivity Tests N-Acetylmuramoyl-L-alanine Amidase Gram-Positive Bacteria Anti-Bacterial Agents Vancomycin-Resistant Enterococci Microbiology in the medical area multidrug-resistant pathogens Vancomycin Drug Resistance Multiple Bacterial Mikrobiologi inom det medicinska området antibiotic synergy |
| Zdroj: | Proceedings of the National Academy of Sciences. 119 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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