Design, Synthesis, and Properties of a Potent Inhibitor of Pseudomonas aeruginosa Deacetylase LpxC

J Med Chem. 2017 Jun 22;60(12):5002-5014. doi: 10.1021/acs.jmedchem.7b00377.

Grazia Piizzi, David T Parker, Yunshan Peng, Markus Dobler, Anup Patnaik, Som Wattanasin, Eugene Liu, Francois Lenoir, Jill Nunez, John Kerrigan, David McKenney ¹, Colin Osborne ¹, Donghui Yu ¹, Leanne Lanieri ¹, Jade Bojkovic ¹, JoAnn Dzink-Fox ¹, Maria-Dawn Lilly ¹, Elizabeth R Sprague, Yipin Lu, Hongming Wang, Srijan Ranjitkar ¹, Lili Xie ¹, Bing Wang, Meir Glick, Lawrence G Hamann, Ruben Tommasi, Xia Yang ¹, Charles R Dean ¹

Affiliations

Affiliation

1 Infectious Diseases Area, Novartis Institutes for BioMedical Research , Emeryville, California 94608, United States.

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

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.

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