7ok1

Crystal structure of Pseudomonas aeruginosa LpxA in complex with compound 3

spinqualitylabelsall models 7ok1, resolution 1.92Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7ok1 is a 3 chain structure with sequence from Pseudomonas aeruginosa PA7. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.92Å Ligands: CL, VFN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function LPXA_PSEAE Involved in the biosynthesis of lipid A, a phosphorylated glycolipid that anchors the lipopolysaccharide to the outer membrane of the cell. Publication Abstract from PubMed This study describes a novel series of UDP-N-acetylglucosamine acyltransferase (LpxA) inhibitors that was identified through affinity-mediated selection from a DNA-encoded compound library. The original hit was a selective inhibitor of Pseudomonas aeruginosa LpxA with no activity against Escherichia coli LpxA. The biochemical potency of the series was optimized through an X-ray crystallography-supported medicinal chemistry program, resulting in compounds with nanomolar activity against P. aeruginosa LpxA (best half-maximal inhibitory concentration (IC50) <5 nM) and cellular activity against P. aeruginosa (best minimal inhibitory concentration (MIC) of 4 mug/mL). Lack of activity against E. coli was maintained (IC50 > 20 muM and MIC > 128 mug/mL). The mode of action of analogues was confirmed through genetic analyses. As expected, compounds were active against multidrug-resistant isolates. Further optimization of pharmacokinetics is needed before efficacy studies in mouse infection models can be attempted. To our knowledge, this is the first reported LpxA inhibitor series with selective activity against P. aeruginosa. Discovery of Novel UDP-N-Acetylglucosamine Acyltransferase (LpxA) Inhibitors with Activity against Pseudomonas aeruginosa.,Ryan MD, Parkes AL, Corbett D, Dickie AP, Southey M, Andersen OA, Stein DB, Barbeau OR, Sanzone A, Thommes P, Barker J, Cain R, Compper C, Dejob M, Dorali A, Etheridge D, Evans S, Faulkner A, Gadouleau E, Gorman T, Haase D, Holbrow-Wilshaw M, Krulle T, Li X, Lumley C, Mertins B, Napier S, Odedra R, Papadopoulos K, Roumpelakis V, Spear K, Trimby E, Williams J, Zahn M, Keefe AD, Zhang Y, Soutter HT, Centrella PA, Clark MA, Cuozzo JW, Dumelin CE, Deng B, Hunt A, Sigel EA, Troast DM, DeJonge BLM J Med Chem. 2021 Sep 27. doi: 10.1021/acs.jmedchem.1c00888. PMID:34569791 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also UDP-N-acetylglucosamine acyltransferase

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