A γ-Lactam Siderophore Antibiotic Effective Against Multidrug-Resistant Gram-Negative Bacilli

Treatment of multidrug resistant Gram-negative (Gr-) bacterial pathogens represent a critical clinical need. Here we report on a novel γ -lactam pyrazolidinone that targets penicillin binding protein (PBPs) and incorporates a siderophore moiety to facilitate uptake into the periplasm. The MIC values...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2020-06, Vol.63 (11), p.5990-6002
Main Authors: Goldberg, Joel, Nguyen, Ha, Kumar, Vijay, Spencer, Elizabeth, Hoyer, Denton, Marshall, Emma, Cmolik, Anna, O'Shea, Margaret, Marshall, Steven, Hujer, Andrea, Hujer, Kristine, Rudin, Susan D, Domitrovic, T Nicholas, Bethel, Christopher, Papp-Wallace, Krisztina M, Logan, Latania, Perez, Federico, Jacobs, Michael, van Duin, David, Kreiswirth, Barry, Bonomo, Robert A, Plummer, Mark, van den Akker, Focco
Format: Article
Language:English
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Summary:Treatment of multidrug resistant Gram-negative (Gr-) bacterial pathogens represent a critical clinical need. Here we report on a novel γ -lactam pyrazolidinone that targets penicillin binding protein (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 drug-like characteristics and mouse PK data are described along with the X-ray crystal structure of 1 binding to its target PBP3.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.0c00255