2. Academic Validation
  3. A γ-Lactam Siderophore Antibiotic Effective against Multidrug-Resistant Gram-Negative Bacilli

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

  • J Med Chem. 2020 Jun 11;63(11):5990-6002. doi: 10.1021/acs.jmedchem.0c00255.
Joel A Goldberg 1,  Ha Nguyen 2,  Vijay Kumar 2,  Elizabeth J Spencer 3,  Denton Hoyer 3,  Emma K Marshall 1,  Anna Cmolik 1,  Margaret O'Shea 1,  Steven H Marshall 1,  Andrea M Hujer 1 4,  Kristine M Hujer 1 4,  Susan D Rudin 1 4,  T Nicholas Domitrovic 1 4,  Christopher R Bethel 1,  Krisztina M Papp-Wallace 1 2 4,  Latania K Logan 5 6,  Federico Perez 1 4 7,  Michael R Jacobs 4 8,  David van Duin 9,  Barry M Kreiswirth 10,  Robert A Bonomo 1 2 4 7 11 12,  Mark S Plummer 3,  Focco van den Akker 2
Affiliations

Affiliations

  • 1 Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio 44106, United States.
  • 2 Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio 44106, United States.
  • 3 Yale Center for Molecular Discovery, West Haven, Connecticut 06516, United States.
  • 4 Department of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, United States.
  • 5 Department of Pediatrics, Rush University Medical Center, Rush Medical College, Chicago, Illinois 60612, United States.
  • 6 Cook County Health and Hospital Systems, Chicago, Illinois 60612, United States.
  • 7 Geriatric Research, Education and Clinical Center, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio 44106, United States.
  • 8 Department of Pathology, University Hospitals Cleveland Medical Center, Division of Clinical Microbiology, Cleveland, Ohio 44106, United States.
  • 9 University of North Carolina School of Medicine, Chapel Hill, North Carolina 27514, United States.
  • 10 Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey 07601, United States.
  • 11 Departments of Pharmacology, Molecular Biology & Microbiology, and Proteomics & Bioinformatics, Case Western Reserve University, Cleveland, Ohio 44106, United States.
  • 12 CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES), Cleveland, Ohio 44106, United States.
PMID: 32420736 DOI: 10.1021/acs.jmedchem.0c00255
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.

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