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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Anti-Bacterial Agents / chemical synthesis
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Anti-Bacterial Agents / metabolism
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Anti-Bacterial Agents / pharmacokinetics
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Anti-Bacterial Agents / pharmacology*
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Bacterial Proteins / antagonists & inhibitors
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Bacterial Proteins / metabolism
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Binding Sites
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Catalytic Domain
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Crystallography, X-Ray
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Drug Resistance, Multiple, Bacterial / drug effects*
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Gram-Negative Bacteria / drug effects
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Half-Life
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Lactams / chemistry*
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Lactams / metabolism
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Lactams / pharmacokinetics
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Lactams / pharmacology
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Mice
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Microbial Sensitivity Tests
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Molecular Docking Simulation
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Penicillin-Binding Proteins / antagonists & inhibitors
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Penicillin-Binding Proteins / metabolism
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Pseudomonas aeruginosa / metabolism
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Siderophores / chemistry*
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Siderophores / metabolism
Substances
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Anti-Bacterial Agents
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Bacterial Proteins
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Lactams
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Penicillin-Binding Proteins
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Siderophores