A gamma-Lactam Siderophore Antibiotic Effective against Multidrug-Resistant Gram-Negative Bacilli

摘要

Treatment of multidrug-resistant Gram-negative bacterial pathogens represents a critical clinical need. Here, we report a novel gamma-lactam pyrazolidinone that targets penicillin-binding proteins (PBPs) and incorporates a siderophore moiety to facilitate uptake into the periplasm. The MIC values of gamma-lactam YU253434, 1, are reported along with the finding that 1 is resistant to hydrolysis by all four classes of beta-lactamases. The druglike characteristics and mouse PK data are described along with the X-ray crystal structure of 1 binding to its target PBP3.