期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 220, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2021.113436
关键词
gamma-Lactam; Siderophore; Multidrug-resistant gram-negative pathogens; Penicillin-binding protein
资金
- Program in Innovative Therapeutics for Connecticut's Health by the Connecticut Bioscience Innovation Fund
- National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH) [R01AI100560, R01AI063517, R01AI072219, UM1AI104681]
- Cleveland Department of Veterans Affairs [1I01BX002872, 1I01BX001974]
- Biomedical Laboratory Research & Development Service of the VA Office of Research and Development
- Geriatric Research Education and Clinical Center VISN 10
- National Institutes of Health [R01AI090155]
- National Institutes of Health through Duke University
- NIAID [75N93019D00022, 75N93020F00001, HHSN272201700020I, 75N93020F00159]
- U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]
- DOE Office of Biological and Environmental Research
- National Institutes of Health, National Institute of General Medical Sciences [P41GM103393]
This study demonstrates the preclinical evaluation of a novel γ-lactam siderophore antibiotic, YU253911, showing potent antimicrobial activity against multidrug-resistant Gram-negative pathogens. The compound targets penicillin-binding protein 3 in Pseudomonas aeruginosa and has dose-dependent efficacy in a mouse infection model. Additionally, a combination with a novel beta-lactamase inhibitor was shown to enhance the effectiveness of the antibiotic against carbapenem-resistant Acinetobacter spp.
Serious infections caused by multidrug-resistant (MDR) organisms (Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii) present a critical need for innovative drug development. Herein, we describe the preclinical evaluation of YU253911, 2, a novel g-lactam siderophore antibiotic with potent antimicrobial activity against MDR Gram-negative pathogens. Penicillin-binding protein (PBP) 3 was shown to be a target of 2 using a binding assay with purified P. aeruginosa PBP3. The specific binding interactions with P. aeruginosa were further characterized with a high-resolution (2.0 A) X-ray structure of the compound's acylation product in P. aeruginosa PBP3. Compound 2 was shown to have a concentration >1 mg/ml at the 6 h time point when administered intravenously or subcutaneously in mice. Employing a meropenem resistant strain of P. aeruginosa, 2 was shown to have dose-dependent efficacy at 50 and 100 mg/kg q6h dosing in a mouse thigh infection model. Lastly, we showed that a novel gamma-lactam and beta-lactamase inhibitor (BLI) combination can effectively lower minimum inhibitory concentrations (MICs) against carbapenem resistant Acinetobacter spp. that demonstrated decreased susceptibility to 2 alone. (C) 2021 Published by Elsevier Masson SAS.
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