7lc4
Crystal structure of Pseudomonas aeruginosa PBP3 in complex with gamma-lactam YU253911Crystal structure of Pseudomonas aeruginosa PBP3 in complex with gamma-lactam YU253911
Structural highlights
Publication Abstract from PubMedSerious 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 gamma-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 mug/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. A gamma-lactam siderophore antibiotic effective against multidrug-resistant Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter spp.,Goldberg JA, Kumar V, Spencer EJ, Hoyer D, Marshall SH, Hujer AM, Hujer KM, Bethel CR, Papp-Wallace KM, Perez F, Jacobs MR, van Duin D, Kreiswirth BN, van den Akker F, Plummer MS, Bonomo RA Eur J Med Chem. 2021 Apr 8;220:113436. doi: 10.1016/j.ejmech.2021.113436. PMID:33933754[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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