A γ-Lactam Siderophore Antibiotic Effective against Multidrug-Resistant Gram-Negative Bacilli.
Basic Information
ID: ALA4602731
Journal: J Med Chem
Title: A γ-Lactam Siderophore Antibiotic Effective against Multidrug-Resistant Gram-Negative Bacilli.
Authors: Goldberg JA, Nguyen H, Kumar V, Spencer EJ, Hoyer D, Marshall EK, Cmolik A, O'Shea M, Marshall SH, Hujer AM, Hujer KM, Rudin SD, Domitrovic TN, Bethel CR, Papp-Wallace KM, Logan LK, Perez F, Jacobs MR, van Duin D, Kreiswirth BM, Bonomo RA, Plummer MS, van den Akker F.
Abstract: Treatment of multidrug-resistant Gram-negative bacterial pathogens represents a critical clinical need. Here, we report a novel γ-lactam pyrazolidinone that targets penicillin-binding proteins (PBPs) and incorporates a siderophore moiety to facilitate uptake into the periplasm. The MIC values of γ-lactam YU253434, 1, are reported along with the finding that 1 is resistant to hydrolysis by all four classes of β-lactamases. The druglike characteristics and mouse PK data are described along with the X-ray crystal structure of 1 binding to its target PBP3.
CiteXplore: 32420736
DOI: 10.1021/acs.jmedchem.0c00255
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