7LC4

Crystal structure of Pseudomonas aeruginosa PBP3 in complex with gamma-lactam YU253911

Summary for 7LC4

• Entry DOI: 10.2210/pdb7lc4/pdb
• Descriptor: Peptidoglycan D,D-transpeptidase FtsI, 1-[(2S)-2-{[(2Z)-2-(2-amino-5-chloro-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-oxopropyl]-4-{[2-(5,6-dihydroxy-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]carbamoyl}-2,5-dihydro-1H-pyrazole-3-carboxylic acid (3 entities in total)
• Functional Keywords: pbp3, gamma-lactam, inhibitor complex, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Pseudomonas aeruginosa
• Total number of polymer chains: 1
• Total formula weight: 59052.52

Authors

van den Akker, F.,Kumar, V. (deposition date: 2021-01-09, release date: 2021-04-28, Last modification date: 2024-10-23)

Primary citation

Goldberg, J.A.,Kumar, V.,Spencer, E.J.,Hoyer, D.,Marshall, S.H.,Hujer, A.M.,Hujer, K.M.,Bethel, C.R.,Papp-Wallace, K.M.,Perez, F.,Jacobs, M.R.,van Duin, D.,Kreiswirth, B.N.,van den Akker, F.,Plummer, M.S.,Bonomo, R.A.
A gamma-lactam siderophore antibiotic effective against multidrug-resistant Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter spp.
Eur.J.Med.Chem., 220:113436-113436, 2021

PubMed Abstract: 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 γ-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 Å) X-ray structure of the compound's acylation product in P. aeruginosa PBP3. Compound 2 was shown to have a concentration >1 μg/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 γ-lactam and β-lactamase inhibitor (BLI) combination can effectively lower minimum inhibitory concentrations (MICs) against carbapenem resistant Acinetobacter spp. that demonstrated decreased susceptibility to 2 alone.

PubMed: 33933754
DOI: 10.1016/j.ejmech.2021.113436

Experimental method

X-RAY DIFFRACTION (2 Å)