A γ-lactam siderophore antibiotic effective against multidrug-resistant Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter spp

• Published in: European journal of medicinal chemistry 2021-08, Vol.220, p.113436-113436, Article 113436
• Main Authors: Goldberg, Joel A., Kumar, Vijay, Spencer, Elizabeth J., Hoyer, Denton, Marshall, Steven H., Hujer, Andrea M., Hujer, Kristine M., Bethel, Christopher R., Papp-Wallace, Krisztina M., Perez, Federico, Jacobs, Michael R., van Duin, David, Kreiswirth, Barry N., van den Akker, Focco, Plummer, Mark S., Bonomo, Robert A.
• Format: Article
• Language: English
• Subjects: Acinetobacter baumannii - drug effects; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Dose-Response Relationship, Drug; Drug Resistance, Multiple, Bacterial - drug effects; Klebsiella pneumoniae - drug effects; Lactams - chemical synthesis; Lactams - chemistry; Lactams - pharmacology; Microbial Sensitivity Tests; Molecular Structure; Multidrug-resistant gram-negative pathogens; Penicillin-binding protein; Pseudomonas aeruginosa - drug effects; Siderophore; Siderophores - chemical synthesis; Siderophores - chemistry; Siderophores - pharmacology; Structure-Activity Relationship; γ-Lactam
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2021.113436

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. [Display omitted] •Multidrug resistance to antibiotics is a challenging global health threat.•A γ-Lactam antibiotic was designed active vs. Pseudomonas aeruginosa and Klebsiella spp.•YU253911 and sulbactam are active against carbapenem resistant Acinetobacter spp.•YU253911 formed an acylation complex to PBP3 of P. aeruginosa (2 Å).•In a murine infection model, YU253911 demonstrated efficacy at 50 and 100 mg/kg.