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

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 lipopolysaccharid...

Full description

Saved in:
Bibliographic Details
Published in:Journal of the American Chemical Society 2020-03, Vol.142 (9), p.4445-4455
Main Authors: Han, Wooseok, Ma, Xiaolei, Balibar, Carl J, Baxter Rath, Christopher M, Benton, Bret, Bermingham, Alun, Casey, Fergal, Chie-Leon, Barbara, Cho, Min-Kyu, Frank, Andreas O, Frommlet, Alexandra, Ho, Chi-Min, Lee, Patrick S, Li, Min, Lingel, Andreas, Ma, Sylvia, Merritt, Hanne, Ornelas, Elizabeth, De Pascale, Gianfranco, Prathapam, Ramadevi, Prosen, Katherine R, Rasper, Dita, Ruzin, Alexey, Sawyer, William S, Shaul, Jacob, Shen, Xiaoyu, Shia, Steven, Steffek, Micah, Subramanian, Sharadha, Vo, Jason, Wang, Feng, Wartchow, Charles, Uehara, Tsuyoshi
Format: Article
Language:English
Subjects:
Acyltransferases - antagonists & inhibitors
Acyltransferases - metabolism
Anti-Bacterial Agents - metabolism
Anti-Bacterial Agents - pharmacology
Crystallography, X-Ray
Enzyme Inhibitors - metabolism
Enzyme Inhibitors - pharmacology
Escherichia coli - drug effects
Escherichia coli - enzymology
Imidazoles - metabolism
Imidazoles - pharmacology
Microbial Sensitivity Tests
Protein Binding
Pyrazoles - metabolism
Pyrazoles - pharmacology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0002-7863
1520-5126
DOI:10.1021/jacs.9b13530