2. Academic Validation
  3. Potentiating Activity of GmhA Inhibitors on Gram-Negative Bacteria

Potentiating Activity of GmhA Inhibitors on Gram-Negative Bacteria

  • J Med Chem. 2024 Apr 25;67(8):6610-6623. doi: 10.1021/acs.jmedchem.4c00037.
François Moreau 1,  Dmytro Atamanyuk 1,  Markus Blaukopf 2,  Marek Barath 2 3,  Mihály Herczeg 2 4,  Nuno M Xavier 2 5,  Jérôme Monbrun 6,  Etienne Airiau 6,  Vivien Henryon 6,  Frédéric Leroy 7,  Stéphanie Floquet 1,  Damien Bonnard 1,  Robert Szabla 8,  Chris Brown 8,  Murray S Junop 8,  Paul Kosma 2,  Vincent Gerusz 1
Affiliations

Affiliations

  • 1 Mutabilis, 102 Avenue Gaston Roussel, Romainville 93230, France.
  • 2 Department of Chemistry, University of Natural Resources and Life Sciences, Muthgasse 18, Vienna A-1190, Austria.
  • 3 Institute of Chemistry, Center for Glycomics, Slovak Academy of Sciences, Dúbravská cesta 9, Bratislava SK-845 38, Slovakia.
  • 4 Department of Pharmaceutical Chemistry, University of Debrecen, Debrecen 4032, Hungary.
  • 5 Centro de Química Estrutural, Institute of Molecular Sciences, Faculdade de Ciências, Universidade de Lisboa, Ed. C8, 5° Piso, Campo Grande, Lisboa 1749-016, Portugal.
  • 6 Activation, 10 Rue Jacquard, Chassieu 69680, France.
  • 7 Carbosynth Limited, 8&9 Old Station Business Park, Compton, Berkshire RG20 6NE, U.K.
  • 8 Department of Biochemistry, University of Western Ontario, London, ON N6A 3K7, Canada.
PMID: 38598312 DOI: 10.1021/acs.jmedchem.4c00037
Abstract

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 Zn2+ 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 Zn2+ 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.

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