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

Joel A. Goldberg, Vijay Kumar, Elizabeth J. Spencer, Denton Hoyer, Steven H. Marshall, Andrea M. Hujer, Kristine M. Hujer, Christopher R. Bethel, Krisztina M. Papp-Wallace, Federico Perez, Michael R. Jacobs, David van Duin, Barry N. Kreiswirth, Focco van den Akker, Mark S. Plummer, Robert A. Bonomo

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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.

Original languageEnglish (US)
Article number113436
JournalEuropean Journal of Medicinal Chemistry
Volume220
DOIs
StatePublished - Aug 5 2021
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Keywords

  • Multidrug-resistant gram-negative pathogens
  • Penicillin-binding protein
  • Siderophore
  • γ-Lactam

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