7DEN

Crystal structure of P.aeruginosa LpxC in complex with inhibitor

Summary for 7DEN

• Entry DOI: 10.2210/pdb7den/pdb
• Descriptor: UDP-3-O-acyl-N-acetylglucosamine deacetylase, ZINC ION, 4-[(1~{R},5~{S})-6-[2-[4-[3-[[2-[(1~{S})-1-oxidanylethyl]imidazol-1-yl]methyl]-1,2-oxazol-5-yl]phenyl]ethynyl]-3-azabicyclo[3.1.0]hexan-3-yl]butanoic acid, ... (4 entities in total)
• Functional Keywords: udp-3-o-acyl-n-acetylglucosamine deacetylase enva, lpxc, pseudomonas aeruginosa, hydrolase
• Biological source: Pseudomonas aeruginosa PAO1
• Total number of polymer chains: 1
• Total formula weight: 33672.55

Authors

Mima, M.,Ushiyama, F.,Takashima, H. (deposition date: 2020-11-04, release date: 2021-01-13, Last modification date: 2023-11-29)

Primary citation

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.
Lead optimization of 2-hydroxymethyl imidazoles as non-hydroxamate LpxC inhibitors: Discovery of TP0586532.
Bioorg.Med.Chem., 30:115964-115964, 2020

PubMed Abstract: Infectious 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.

PubMed: 33385955
DOI: 10.1016/j.bmc.2020.115964

Experimental method

X-RAY DIFFRACTION (2.07 Å)