6P9P

E.coli LpxA in complex with Compound 1

Summary for 6P9P

• Entry DOI: 10.2210/pdb6p9p/pdb
• Descriptor: Acyl-[acyl-carrier-protein]--UDP-N-acetylglucosamine O-acyltransferase, PHOSPHATE ION, DIMETHYL SULFOXIDE, ... (5 entities in total)
• Functional Keywords: acyltransferase, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Escherichia coli
• Total number of polymer chains: 1
• Total formula weight: 29770.65

Authors

Ma, X.,Shia, S.,Ornelas, E. (deposition date: 2019-06-10, release date: 2020-03-11, Last modification date: 2023-10-11)

Primary citation

Han, W.,Ma, X.,Balibar, C.J.,Baxter Rath, C.M.,Benton, B.,Bermingham, A.,Casey, F.,Chie-Leon, B.,Cho, M.K.,Frank, A.O.,Frommlet, A.,Ho, C.M.,Lee, P.S.,Li, M.,Lingel, A.,Ma, S.,Merritt, H.,Ornelas, E.,De Pascale, G.,Prathapam, R.,Prosen, K.R.,Rasper, D.,Ruzin, A.,Sawyer, W.S.,Shaul, J.,Shen, X.,Shia, S.,Steffek, M.,Subramanian, S.,Vo, J.,Wang, F.,Wartchow, C.,Uehara, T.
Two Distinct Mechanisms of Inhibition of LpxA Acyltransferase Essential for Lipopolysaccharide Biosynthesis.
J.Am.Chem.Soc., 142:4445-4455, 2020

PubMed Abstract: The lipopolysaccharide biosynthesis pathway is considered an attractive drug target against the rising threat of multi-drug-resistant Gram-negative bacteria. Here, we report two novel small-molecule inhibitors (compounds and ) of the acyltransferase LpxA, the first enzyme in the lipopolysaccharide biosynthesis pathway. We show genetically that the antibacterial activities of the compounds against efflux-deficient are mediated by LpxA inhibition. Consistently, the compounds inhibited the LpxA enzymatic reaction in vitro. Intriguingly, using biochemical, biophysical, and structural characterization, we reveal two distinct mechanisms of LpxA inhibition; compound is a substrate-competitive inhibitor targeting apo LpxA, and compound is an uncompetitive inhibitor targeting the LpxA/product complex. Compound exhibited more favorable biological and physicochemical properties than compound and was optimized using structural information to achieve improved antibacterial activity against wild-type . These results show that LpxA is a promising antibacterial target and imply the advantages of targeting enzyme/product complexes in drug discovery.

PubMed: 32064871
DOI: 10.1021/jacs.9b13530

Experimental method

X-RAY DIFFRACTION (2 Å)