Potentiating Activity of GmhA Inhibitors on Gram-Negative Bacteria.

Autor: Moreau F; Mutabilis, 102 Avenue Gaston Roussel, Romainville 93230, France., Atamanyuk D; Mutabilis, 102 Avenue Gaston Roussel, Romainville 93230, France., Blaukopf M; Department of Chemistry, University of Natural Resources and Life Sciences, Muthgasse 18, Vienna A-1190, Austria., Barath M; Department of Chemistry, University of Natural Resources and Life Sciences, Muthgasse 18, Vienna A-1190, Austria.; Institute of Chemistry, Center for Glycomics, Slovak Academy of Sciences, Dúbravská cesta 9, Bratislava SK-845 38, Slovakia., Herczeg M; Department of Chemistry, University of Natural Resources and Life Sciences, Muthgasse 18, Vienna A-1190, Austria.; Department of Pharmaceutical Chemistry, University of Debrecen, Debrecen 4032, Hungary., Xavier NM; Department of Chemistry, University of Natural Resources and Life Sciences, Muthgasse 18, Vienna A-1190, Austria.; Centro de Química Estrutural, Institute of Molecular Sciences, Faculdade de Ciências, Universidade de Lisboa, Ed. C8, 5° Piso, Campo Grande, Lisboa 1749-016, Portugal., Monbrun J; Activation, 10 Rue Jacquard, Chassieu 69680, France., Airiau E; Activation, 10 Rue Jacquard, Chassieu 69680, France., Henryon V; Activation, 10 Rue Jacquard, Chassieu 69680, France., Leroy F; Carbosynth Limited, 8&9 Old Station Business Park, Compton, Berkshire RG20 6NE, U.K., Floquet S; Mutabilis, 102 Avenue Gaston Roussel, Romainville 93230, France., Bonnard D; Mutabilis, 102 Avenue Gaston Roussel, Romainville 93230, France., Szabla R; Department of Biochemistry, University of Western Ontario, London, ON N6A 3K7, Canada., Brown C; Department of Biochemistry, University of Western Ontario, London, ON N6A 3K7, Canada., Junop MS; Department of Biochemistry, University of Western Ontario, London, ON N6A 3K7, Canada., Kosma P; Department of Chemistry, University of Natural Resources and Life Sciences, Muthgasse 18, Vienna A-1190, Austria., Gerusz V; Mutabilis, 102 Avenue Gaston Roussel, Romainville 93230, France.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2024 Apr 25; Vol. 67 (8), pp. 6610-6623. Date of Electronic Publication: 2024 Apr 10.
DOI: 10.1021/acs.jmedchem.4c00037
Abstrakt: Inhibition of the biosynthesis of bacterial heptoses opens novel perspectives for antimicrobial therapies. The enzyme GmhA responsible for the first committed biosynthetic step catalyzes the conversion of sedoheptulose 7-phosphate into d- glycero -d- manno -heptose 7-phosphate and harbors a Zn 2+ ion in the active site. A series of phosphoryl- and phosphonyl-substituted derivatives featuring a hydroxamate moiety were designed and prepared from suitably protected ribose or hexose derivatives. High-resolution crystal structures of GmhA complexed to two N -formyl hydroxamate inhibitors confirmed the binding interactions to a central Zn 2+ ion coordination site. Some of these compounds were found to be nanomolar inhibitors of GmhA. While devoid of HepG2 cytotoxicity and antibacterial activity of their own, they demonstrated in vitro lipopolysaccharide heptosylation inhibition in Enterobacteriaceae as well as the potentiation of erythromycin and rifampicin in a wild-type Escherichia coli strain. These inhibitors pave the way for a novel treatment of Gram-negative infections.
Databáze: MEDLINE
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