title: Targeting DXP synthase in human pathogens: enzyme inhibition and antimicrobial activity of butylacetylphosphonate.
abstract: The unique methylerythritol phosphate 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 and 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.
authors.affiliation: Department of Pharmacology and Molecular Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Smith
authors.affiliation: Deptartment of Chemistry and Biochemistry, Northern Arizona University, Flagstaff, AZ, USA.
authors.forename: Nicole V
authors.initials: NV
authors.lastname: Warrington
authors.affiliation: Department of Pharmacology and Molecular Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Vierling
authors.affiliation: Center for Structural Genomics of Infectious Diseases, Northwestern Feinberg School of Medicine, Department of Molecular Pharmacology and Biological Chemistry, Chicago, IL, USA.
authors.forename: Misty L
authors.initials: ML
authors.lastname: Kuhn
authors.affiliation: Center for Structural Genomics of Infectious Diseases, Northwestern Feinberg School of Medicine, Department of Molecular Pharmacology and Biological Chemistry, Chicago, IL, USA.
authors.forename: Wayne F
authors.initials: WF
authors.lastname: Anderson
authors.affiliation: Deptartment of Chemistry and Biochemistry, Northern Arizona University, Flagstaff, AZ, USA.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Koppisch
authors.affiliation: Department of Pharmacology and Molecular Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Caren L
authors.initials: CL
authors.lastname: Freel Meyers
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000201:enzymology; D006094:Gram-Positive Bacteria / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D058990:Molecular Targeted Therapy; D063065:Organophosphonates / Q000494:pharmacology*; D014166:Transferases / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D063065:Organophosphonates; C587183:butylacetylphosphonate; D014166:Transferases; C109461:deoxyxylulose-5-phosphate synthase