2. Academic Validation
  3. Structural Insights into the Inhibition of Undecaprenyl Pyrophosphate Synthase from Gram-Positive Bacteria

Structural Insights into the Inhibition of Undecaprenyl Pyrophosphate Synthase from Gram-Positive Bacteria

  • J Med Chem. 2021 Sep 23;64(18):13540-13550. doi: 10.1021/acs.jmedchem.1c00941.
Sean D Workman 1 2,  Jonathan Day 3,  Maya A Farha 4 5,  Sara S El Zahed 4 5,  Chris Bon 1 2,  Eric D Brown 4 5,  Michael G Organ 3 6 7,  Natalie C J Strynadka 1 2
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada.
  • 2 Centre for Blood Research, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada.
  • 3 Department of Chemistry, York University, 4700 Keele Street, Toronto, Ontario M3J 1P3, Canada.
  • 4 Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada.
  • 5 Michael G. DeGroote Institute of Infectious Disease Research, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4L8, Canada.
  • 6 Centre for Catalysis Research and Innovation, University of Ottawa, 30 Marie-Curie Private, Ottawa, Ontario K1N 6N5, Canada.
  • 7 Department of Chemistry and Biomolecular Sciences, University of Ottawa, 150 Louis-Pasteur Private, Ottawa, Ontario K1N 6N5, Canada.
PMID: 34473495 DOI: 10.1021/acs.jmedchem.1c00941
Abstract

The polyprenyl lipid undecaprenyl phosphate (C55P) is the universal carrier lipid for the biosynthesis of Bacterial cell wall Polymers. C55P is synthesized in its pyrophosphate form by undecaprenyl pyrophosphate synthase (UppS), an essential cis-prenyltransferase that is an attractive target for Antibiotic development. We previously identified a compound (MAC-0547630) that showed promise as a novel class of inhibitor and an ability to potentiate β-lactam Antibiotics. Here, we provide a structural model for MAC-0547630's inhibition of UppS and a structural rationale for its enhanced effect on UppS from Bacillus subtilis versus Staphylococcus aureus. We also describe the synthesis of a MAC-0547630 derivative (JPD447), show that it too can potentiate β-lactam Antibiotics, and provide a structural rationale for its improved potentiation. Finally, we present an improved structural model of clomiphene's inhibition of UppS. Taken together, our data provide a foundation for structure-guided drug design of more potent UppS inhibitors in the future.

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