7dem
Crystal structure of P.aeruginosa LpxC in complex with inhibitorCrystal structure of P.aeruginosa LpxC in complex with inhibitor
Structural highlights
FunctionLPXC_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 PubMedInfectious diseases caused by resistant Gram-negative bacteria have become a serious problem, and the development of therapeutic drugs with a novel mechanism of action and that do not exhibit cross-resistance with existing drugs has been earnestly desired. UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) is a drug target that has been studied for a long time. However, no LpxC inhibitors are available on the market at present. In this study, we sought to create a new antibacterial agent without a hydroxamate moiety, which is a common component of the major LpxC inhibitors that have been reported to date and that may cause toxicity. As a result, a development candidate, TP0586532, was created that is effective against carbapenem-resistant Klebsiella pneumoniae and does not pose a cardiovascular risk. Lead optimization of 2-hydroxymethyl imidazoles as non-hydroxamate LpxC inhibitors: Discovery of TP0586532.,Ushiyama F, Takashima H, Matsuda Y, Ogata Y, Sasamoto N, Kurimoto-Tsuruta R, Ueki K, Tanaka-Yamamoto N, Endo M, Mima M, Fujita K, Takata I, Tsuji S, Yamashita H, Okumura H, Otake K, Sugiyama H Bioorg Med Chem. 2020 Dec 29;30:115964. doi: 10.1016/j.bmc.2020.115964. PMID:33385955[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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