A γ-Lactam Siderophore Antibiotic Effective against Multidrug-Resistant Gram-Negative Bacilli
Joel Goldberg, Ha Nguyen, Vijay Kumar, Elizabeth J. Spencer, Denton Hoyer, Emma Marshall, Anna Cmolik, Margaret O’Shea, Steven H. Marshall, Andrea M. Hujer, Kristine M. Hujer, Susan D. Rudin, Tatiana Domitrovic, Christopher R. Bethel, Krisztina M. Papp‐Wallace, Latania K. Logan, Federico Pérez, Michael R. Jacobs, David van Duin, Barry M. Kreiswirth, Robert A. Bonomo, Mark S. Plummer, Focco van den Akker
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.