5U3B

Pseudomonas aeruginosa LpxC in complex with NVS-LPXC-01

Summary for 5U3B

• Entry DOI: 10.2210/pdb5u3b/pdb
• Related: 5U39
• Descriptor: UDP-3-O-acyl-N-acetylglucosamine deacetylase, ZINC ION, N-[(2S)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl]-4-[(but-2-yn-1-yl)oxy]benzamide, ... (5 entities in total)
• Functional Keywords: lpxc, hydroxymate, gram negative, hydrolase
• Biological source: Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1)
• Total number of polymer chains: 2
• Total formula weight: 67571.50

Authors

Sprague, E.R. (deposition date: 2016-12-01, release date: 2017-06-07, Last modification date: 2024-03-06)

Primary citation

Piizzi, G.,Parker, D.T.,Peng, Y.,Dobler, M.,Patnaik, A.,Wattanasin, S.,Liu, E.,Lenoir, F.,Nunez, J.,Kerrigan, J.,McKenney, D.,Osborne, C.,Yu, D.,Lanieri, L.,Bojkovic, J.,Dzink-Fox, J.,Lilly, M.D.,Sprague, E.R.,Lu, Y.,Wang, H.,Ranjitkar, S.,Xie, L.,Wang, B.,Glick, M.,Hamann, L.G.,Tommasi, R.,Yang, X.,Dean, C.R.
Design, Synthesis, and Properties of a Potent Inhibitor of Pseudomonas aeruginosa Deacetylase LpxC.
J. Med. Chem., 60:5002-5014, 2017

PubMed Abstract: Over the past several decades, the frequency of antibacterial resistance in hospitals, including multidrug resistance (MDR) and its association with serious infectious diseases, has increased at alarming rates. Pseudomonas aeruginosa is a leading cause of nosocomial infections, and resistance to virtually all approved antibacterial agents is emerging in this pathogen. To address the need for new agents to treat MDR P. aeruginosa, we focused on inhibiting the first committed step in the biosynthesis of lipid A, the deacetylation of uridyldiphospho-3-O-(R-hydroxydecanoyl)-N-acetylglucosamine by the enzyme LpxC. We approached this through the design, synthesis, and biological evaluation of novel hydroxamic acid LpxC inhibitors, exemplified by 1, where cytotoxicity against mammalian cell lines was reduced, solubility and plasma-protein binding were improved while retaining potent anti-pseudomonal activity in vitro and in vivo.

PubMed: 28549219
DOI: 10.1021/acs.jmedchem.7b00377

Experimental method

X-RAY DIFFRACTION (2 Å)