| Literature DB >> 28549219 |
Grazia Piizzi, David T Parker, Yunshan Peng, Markus Dobler, Anup Patnaik, Som Wattanasin, Eugene Liu, Francois Lenoir, Jill Nunez, John Kerrigan, David McKenney1, Colin Osborne1, Donghui Yu1, Leanne Lanieri1, Jade Bojkovic1, JoAnn Dzink-Fox1, Maria-Dawn Lilly1, Elizabeth R Sprague, Yipin Lu, Hongming Wang, Srijan Ranjitkar1, Lili Xie1, Bing Wang, Meir Glick, Lawrence G Hamann, Ruben Tommasi, Xia Yang1, Charles R Dean1.
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.Entities:
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Year: 2017 PMID： 28549219 DOI： 10.1021/acs.jmedchem.7b00377
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446