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Two Distinct Mechanisms of Inhibition of LpxA Acyltransferase Essential for Lipopolysaccharide Biosynthesis

Ma, Xiaolei and Han, Wooseok and Benson, Timothy and Brenton, Bret and Berminghan, Alun and Casey, Fergal and Chiu, Chun-Hao and Cook, Kim and Frank, Andreas and Frommlet, Alexandra and Ho, Chi-Min and Jansen, Hanneke and Lee, Patrick and Chie Leon, Barbara and Li, Min and Cho, Min-Kyu and Lingel, Andreas and Ma, Sylvia and Merritt, Hanne and Ornelas, Elizabeth and De Pascale, Gianfranco and Prathapam, Ramadevi and Prosen, Katie and Rasper, Dita and Rath, Christopher and Sawyer, William and Shaul, Jacob and Shia, Steven and Steffek, Micah and Smith, Thomas and Subramanian, Sharadha and Vo, Jason and Wang, Feng and Wartchow, Charles and Uehara, Tsuyoshi (2020) Two Distinct Mechanisms of Inhibition of LpxA Acyltransferase Essential for Lipopolysaccharide Biosynthesis. Journal of the American Chemical Society JACS., 142 (9). pp. 4445-4455. ISSN 0002-78631520-5126


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 1 and 2) 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 Escherichia coli 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 1 is a substrate-competitive inhibitor targeting apo LpxA, and compound 2 is an uncompetitive inhibitor targeting the LpxA/product complex. Compound 2 exhibited more favorable biological and physicochemical properties than compound 1 and was optimized using structural information to achieve improved antibacterial activity against wild-type E. coli. These results show that LpxA is a promising antibacterial target and imply the advantages of targeting enzyme/product complexes in drug discovery.

Item Type: Article
Date Deposited: 14 Jul 2020 00:45
Last Modified: 14 Jul 2020 00:45


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