Structural highlights
FunctionLPXC_PSEA8 Catalyzes the hydrolysis of UDP-3-O-myristoyl-N-acetylglucosamine to form UDP-3-O-myristoylglucosamine and acetate, the committed step in lipid A biosynthesis. Publication Abstract from PubMedUDP-3-O-((R)-3-hydroxymyristoyl)-N-glucosamine deacetylase (LpxC) is as an attractive target for the discovery and development of novel antibacterial drugs to address the critical medical need created by multi-drug resistant Gram-negative bacteria. Using a scaffold hopping approach on a known family of methylsulfone hydroxamate LpxC inhibitors, several hit series eliciting potent antibacterial activities against Enterobacteriaceae and Pseudomonas aeruginosa were identified. Subsequent hit-to-lead optimization, using co-crystal structures of inhibitors bound to Pseudomonas aeruginosa LpxC as guides, resulted in the discovery of multiple chemical series based on i) isoindolin-1-ones, ii) 4,5-dihydro-6H-thieno[2,3-c]pyrrol-6-ones and iii) 1,2-dihydro-3H-pyrrolo[1,2-c]imidazole-3-ones. Synthetic methods, antibacterial activities and relative binding affinities, as well as physico-chemical properties that allowed compound prioritization are presented. Finally, in vivo properties of lead molecules which belong to the most promising pyrrolo-imidazolone series such as 18d, are discussed. Discovery of Novel Inhibitors of LpxC Displaying Potent In Vitro Activity against Gram-Negative Bacteria.,Surivet JP, Panchaud P, Specklin JL, Diethelm S, Blumstein AC, Gauvin JC, Jacob L, Masse F, Mathieu G, Mirre A, Schmitt C, Lange R, Tidten-Luksch N, Gnerre C, Seeland S, Herrmann C, Seiler P, Enderlin-Paput M, Mac Sweeney A, Wicki M, Hubschwerlen C, Ritz D, Rueedi G J Med Chem. 2019 Dec 5. doi: 10.1021/acs.jmedchem.9b01604. PMID:31804826[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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