Structural Insights into the Inhibition of Undecaprenyl Pyrophosphate Synthase from Gram-Positive Bacteria
| Autor: | Jonathan Day, Sara S. El Zahed, Chris Bon, Natalie C. J. Strynadka, Michael G. Organ, Eric D. Brown, Maya A. Farha, Sean D. Workman |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Methicillin-Resistant Staphylococcus aureus
medicine.drug_class Gram-positive bacteria Antibiotics Microbial Sensitivity Tests Bacillus subtilis Crystallography X-Ray medicine.disease_cause Pyrophosphate Bacterial cell structure Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Bacterial Proteins Biosynthesis Catalytic Domain Drug Discovery medicine Enzyme Inhibitors 030304 developmental biology 0303 health sciences Alkyl and Aryl Transferases Molecular Structure ATP synthase biology 030306 microbiology biology.organism_classification 3. Good health chemistry Biochemistry Staphylococcus aureus biology.protein Molecular Medicine Protein Binding |
| Zdroj: | Journal of Medicinal Chemistry. 64:13540-13550 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.1c00941 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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