A threat to global health is presently associated with the increase of multidrug-resistant bacteria, for several of which common antibiotics are not effective anymore. Novel approaches, such as the antivirulence concept, are therefore urgently needed to identify bacterial targets and develop appropriate compounds with new modes of action. Various isomers of heptoses play crucial roles in bacteria. Glycero-D-manno-heptoses have been found in capsular polysaccharides, O-antigens and the core region of lipopolysaccharide (LPS). The biosynthesis of heptoses and the nucleotide-activated ADP- and GDP-heptoses has been elucidated in great detail lead. The first enzymatic step common to all pathways is catalyzed by the sedoheptulose-7-phosphate isomerase GmhA, which notably requires a zinc atom for activity.
Starting from suitable ribose and hexose precursors, a series of derivatives, based on GmhA’s open chain substrate sedoheptulose-7-phosphate and a zinc chelating formylhydroxamate scaffold have been prepared as terminal phosphate and phosphonate analogues, some of which were able to interfere with the heptose biosynthesis in a nanomolar concentration range. Bacteria grown in the presence of one of these inhibitors and glucose-6-phosphate to activate the UhpT transport system expressed a deep rough phenotype and were effectively sensitized to erythromycin. These findings further support the search for innovative ways to fight bacterial infections.
- Brown, E. D.; Wright, G. D. Nature 2016, 529, 336.
- Kosma, P. Curr. Org. Chem. 2008, 12, 1021.
- Valvano M. A.; Messner P.; Kosma P. Microbiol. 2002, 148, 1979.
- Harmer, N. J. Mol. Biol. 2010, 400, 379.
- Gerusz, V.; Vincent, S. P.; Oxoby, M.; Atamanyuk, D.; Moreau, F.; Tikad, A.; Andaloussi, M. WO2012073214 (2010); Atamanyuk, D.; Gerusz, V. WO2013178622 (2013); Atamanyuk, D.; Gerusz, V.; Moreau, F.; Henryon, V.; Monbrun, J.; Airiau, E. WO2014067904A1 (2014).
- Durka, M.; Tikad, A.; Périon, R.; Bosco, M.; Andaloussi, M.; Floquet, S.; Malacain, E.; Moreau, F.; Oxoby, M.; Gerusz, V.; Vincent, S. P. Chem. Eur. J. 2011, 17, 11305