title: Crystallographic insights into the structure-activity relationships of diazaborine enoyl-ACP reductase inhibitors.
abstract: Enoyl-ACP reductase, the last enzyme of the fatty-acid biosynthetic pathway, is the molecular target for several successful antibiotics such as the tuberculosis therapeutic isoniazid. It is currently under investigation as a narrow-spectrum antibiotic target for the treatment of several types of bacterial infections. The diazaborine family is a group of boron heterocycle-based synthetic antibacterial inhibitors known to target enoyl-ACP reductase. Development of this class of molecules has thus far focused solely on the sulfonyl-containing versions. Here, the requirement for the sulfonyl group in the diazaborine scaffold was investigated by examining several recently characterized enoyl-ACP reductase inhibitors that lack the sulfonyl group and exhibit additional variability in substitutions, size and flexibility. Biochemical studies are reported showing the inhibition of Escherichia coli enoyl-ACP reductase by four diazaborines, and the crystal structures of two of the inhibitors bound to E. coli enoyl-ACP reductase solved to 2.07 and 2.11 Å resolution are reported. The results show that the sulfonyl group can be replaced with an amide or thioamide without disruption of the mode of inhibition of the molecule.
authors.affiliation: Department of Chemistry and Biochemistry, California State University Northridge, Northridge, CA 91330-8262, USA.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Jordan
authors.affiliation: Department of Chemistry and Biochemistry, California State University Northridge, Northridge, CA 91330-8262, USA.
authors.forename: Braddock A
authors.initials: BA
authors.lastname: Sandoval
authors.affiliation: Department of Chemistry and Biochemistry, California State University Northridge, Northridge, CA 91330-8262, USA.
authors.forename: Mkrtich V
authors.initials: MV
authors.lastname: Serobyan
authors.affiliation: Department of Biological Sciences, California State University Los Angeles, Los Angeles, CA 90032, USA.
authors.forename: Damian H
authors.initials: DH
authors.lastname: Gilling
authors.affiliation: Department of Chemistry and Biochemistry, California State University East Bay, Hayward, CA 94542-3089, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Groziak
authors.affiliation: Department of Biological Sciences, California State University Los Angeles, Los Angeles, CA 90032, USA.
authors.forename: H Howard
authors.initials: HH
authors.lastname: Xu
authors.affiliation: Department of Chemistry and Biochemistry, California State University Northridge, Northridge, CA 91330-8262, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Vey
mesh_terms: D001372:Aza Compounds / Q000737:chemistry* / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D001665:Binding Sites; D018360:Crystallography, X-Ray; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000302:isolation & purification; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D012996:Solutions; D013329:Structure-Activity Relationship
chemical_list: D001372:Aza Compounds; D004791:Enzyme Inhibitors; D012996:Solutions; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)
keywords: Escherichia coli; NAD; antibiotics; binding sites; boron heterocycle; crystallography; enoyl-ACP reductase; enzyme inhibitors