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A γ-lactam siderophore antibiotic effective against multidrug-resistant Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter spp.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2021 Aug 05; Vol. 220, pp. 113436. Date of Electronic Publication: 2021 Apr 08. - Publication Year :
- 2021
-
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.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2021. Published by Elsevier Masson SAS.)
- Subjects :
- Acinetobacter baumannii drug effects
Anti-Bacterial Agents chemical synthesis
Anti-Bacterial Agents chemistry
Dose-Response Relationship, Drug
Lactams chemical synthesis
Lactams chemistry
Microbial Sensitivity Tests
Molecular Structure
Pseudomonas aeruginosa drug effects
Siderophores chemical synthesis
Siderophores chemistry
Structure-Activity Relationship
Anti-Bacterial Agents pharmacology
Drug Resistance, Multiple, Bacterial drug effects
Klebsiella pneumoniae drug effects
Lactams pharmacology
Siderophores pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 220
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 33933754
- Full Text :
- https://doi.org/10.1016/j.ejmech.2021.113436