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
  • 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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