5u3b
Pseudomonas aeruginosa LpxC in complex with NVS-LPXC-01Pseudomonas aeruginosa LpxC in complex with NVS-LPXC-01
Structural highlights
Function[LPXC_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 PubMedOver 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. Design, Synthesis, and Properties of a Potent Inhibitor of Pseudomonas aeruginosa Deacetylase LpxC.,Piizzi G, Parker DT, 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 MD, Sprague ER, Lu Y, Wang H, Ranjitkar S, Xie L, Wang B, Glick M, Hamann LG, Tommasi R, Yang X, Dean CR J Med Chem. 2017 Jun 22;60(12):5002-5014. doi: 10.1021/acs.jmedchem.7b00377. Epub, 2017 Jun 9. PMID:28549219[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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