7OKB
Crystal structure of Pseudomonas aeruginosa LpxA in complex with compound 45
Summary for 7OKB
| Entry DOI | 10.2210/pdb7okb/pdb |
| Descriptor | Acyl-[acyl-carrier-protein]--UDP-N-acetylglucosamine O-acyltransferase, CHLORIDE ION, SULFATE ION, ... (5 entities in total) |
| Functional Keywords | acyltransferase, fatty acids, lipid a, left-handed parallel beta-helix, transferase |
| Biological source | Pseudomonas aeruginosa |
| Total number of polymer chains | 30 |
| Total formula weight | 868215.25 |
| Authors | Ryan, M.D.,Parkes, A.L.,Southey, M.,Andersen, O.A.,Zahn, M.,Barker, J.,DeJonge, B.L.M. (deposition date: 2021-05-17, release date: 2021-10-06, Last modification date: 2024-01-31) |
| Primary citation | Ryan, M.D.,Parkes, A.L.,Corbett, D.,Dickie, A.P.,Southey, M.,Andersen, O.A.,Stein, D.B.,Barbeau, O.R.,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, A.D.,Zhang, Y.,Soutter, H.T.,Centrella, P.A.,Clark, M.A.,Cuozzo, J.W.,Dumelin, C.E.,Deng, B.,Hunt, A.,Sigel, E.A.,Troast, D.M.,DeJonge, B.L.M. Discovery of Novel UDP- N -Acetylglucosamine Acyltransferase (LpxA) Inhibitors with Activity against Pseudomonas aeruginosa . J.Med.Chem., 64:14377-14425, 2021 Cited by PubMed Abstract: This study describes a novel series of UDP--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 LpxA with no activity against 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 LpxA (best half-maximal inhibitory concentration (IC) <5 nM) and cellular activity against (best minimal inhibitory concentration (MIC) of 4 μg/mL). Lack of activity against was maintained (IC > 20 μM and MIC > 128 μg/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 . PubMed: 34569791DOI: 10.1021/acs.jmedchem.1c00888 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.58 Å) |
Structure validation
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