Targeting DXP synthase in human pathogens: enzyme inhibition and antimicrobial activity of butylacetylphosphonate
| Autor: | Wayne F. Anderson, Ryan J. Vierling, J M Smith, Caren L. Freel Meyers, Andrew T. Koppisch, Misty L. Kuhn, Nicole V. Warrington |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Antiparasitic
medicine.drug_class DXP synthase Organophosphonates medicine.disease_cause Gram-Positive Bacteria 01 natural sciences Article Microbiology 03 medical and health sciences chemistry.chemical_compound isoprenoid biosynthesis Biosynthesis Transferases Drug Discovery Drug Resistance Bacterial Gram-Negative Bacteria medicine Humans Molecular Targeted Therapy Enzyme Inhibitors Escherichia coli 030304 developmental biology Pharmacology chemistry.chemical_classification 0303 health sciences ATP synthase biology 010405 organic chemistry Drug Synergism Antimicrobial biology.organism_classification thiamin diphosphate 3. Good health 0104 chemical sciences Anti-Bacterial Agents Enzyme chemistry Biochemistry selective inhibitor Salmonella enterica biology.protein |
| Zdroj: | The Journal of antibiotics |
| ISSN: | 0021-8820 |
| Popis: | The unique methylerythritol phosphate (MEP) pathway for isoprenoid biosynthesis is essential in most bacterial pathogens. The first enzyme in this pathway, 1-deoxy-D-xylulose 5-phosphate (DXP) synthase, catalyzes a distinct thiamin diphosphate (ThDP)-dependent reaction to form DXP from D-glyceraldehyde 3-phosphate (D-GAP) and pyruvate and represents a potential anti-infective drug target. We have previously demonstrated that the unnatural bisubstrate analog, butylacetylphosphonate (BAP), exhibits selective inhibition of Escherichia coli DXP synthase over mammalian ThDP-dependent enzymes. Here, we report the selective inhibition by BAP against recombinant DXP synthase homologs from Mycobacterium tuberculosis, Yersinia pestis, and Salmonella enterica. We also demonstrate antimicrobial activity of BAP against both Gram-negative and Gram-positive strains (including E. coli, S. enterica, Bacillus anthracis), and several clinically isolated pathogens. Our results suggest a mechanism of action involving inhibition of DXP synthase and show that BAP acts synergistically with established antimicrobial agents, highlighting a potential strategy to combat emerging resistance in bacterial pathogens. |
| Databáze: | OpenAIRE |
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