title: Systematic synthesis of inhibitors of the two first enzymes of the bacterial heptose biosynthetic pathway: towards antivirulence molecules targeting lipopolysaccharide biosynthesis.
abstract: L-Heptoses (L-glycero-D-manno-heptopyranoses) are constituents of the inner core of lipolysaccharide (LPS), a molecule playing key roles in the mortality of many infectious diseases as well as in the virulence of many human pathogens. The inhibition of the first enzymes of the bacterial heptose biosynthetic pathway is an almost unexplored field to date although it appears to be a very novel way for the development of antivirulence drugs. We report the synthesis of a series of D-glycero-D-manno-heptopyranose 7-phosphate (H7P) analogues and their inhibition properties against the isomerase GmhA and the the kinase HldE, the two first enzymes of the bacterial heptose biosynthetic pathway. The heptose structures have been modified at the 1-, 2-, 6- and 7-positions to probe the importance of the key structural features of H7P that allow a tight binding to the target enzymes; H7P being the product of GmhA and the substrate of HldE, the second objective was to find structures that could simultaneously inhibit both enzymes. We found that GmhA and HldE were extremely sensitive to structural modifications at the 6- and 7- positions of the heptose scaffold. To our surprise, the epimeric analogue of H7P displaying a D-glucopyranose configuration was found to be the best inhibitor of both enzymes but also the only molecule of this series that could inhibit GmhA (IC(50)=34 μM) and HldE (IC(50)=9.4 μM) in the low micromolar range. Noteworthy, this study describes the first inhibitors of GmhA ever reported, and paves the way to the design of a second generation of molecules targeting the bacterial virulence.
authors.affiliation: Chemistry Department, University of Namur, rue de Bruxelles 61, 5000 Namur, Belgium.
authors.forename: Maxime
authors.initials: M
authors.lastname: Durka
authors.forename: Abdellatif
authors.initials: A
authors.lastname: Tikad
authors.forename: Régis
authors.initials: R
authors.lastname: Périon
authors.forename: Michael
authors.initials: M
authors.lastname: Bosco
authors.forename: Mounir
authors.initials: M
authors.lastname: Andaloussi
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Floquet
authors.forename: Elodie
authors.initials: E
authors.lastname: Malacain
authors.forename: François
authors.initials: F
authors.lastname: Moreau
authors.forename: Mayalen
authors.initials: M
authors.lastname: Oxoby
authors.forename: Vincent
authors.initials: V
authors.lastname: Gerusz
authors.forename: Stéphane P
authors.initials: SP
authors.lastname: Vincent
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism; D053898:Biosynthetic Pathways; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D004926:Escherichia coli / Q000737:chemistry* / Q000201:enzymology / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000378:metabolism; D006539:Heptoses / Q000096:biosynthesis* / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007535:Isomerases / Q000737:chemistry* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000096:biosynthesis* / Q000737:chemistry* / Q000378:metabolism; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010766:Phosphorylation; D010770:Phosphotransferases / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism; D014774:Virulence
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D006539:Heptoses; D008070:Lipopolysaccharides; D010770:Phosphotransferases; D007535:Isomerases