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Application of Virtual Screening to the Identification of New LpxC Inhibitor Chemotypes, Oxazolidinone and Isoxazoline

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posted on 18.09.2018, 00:00 by Patrick S. Lee, Guillaume Lapointe, Ann Marie Madera, Robert L. Simmons, Wenjian Xu, Aregahegn Yifru, Meiliana Tjandra, Subramanian Karur, Alice Rico, Katherine Thompson, Jade Bojkovic, Lili Xie, Kyoko Uehara, Amy Liu, Wei Shu, Cornelia Bellamacina, David McKenney, Laura Morris, George R. Tonn, Colin Osborne, Bret M. Benton, Laura McDowell, Jiping Fu, Zachary K. Sweeney
This report summarizes the identification and synthesis of novel LpxC inhibitors aided by computational methods that leveraged numerous crystal structures. This effort led to the identification of oxazolidinone and isoxazoline inhibitors with potent in vitro activity against P. aeruginosa and other Gram-negative bacteria. Representative compound 13f demonstrated efficacy against P. aeruginosa in a mouse neutropenic thigh infection model. The antibacterial activity against K. pneumoniae could be potentiated by Gram-positive antibiotics rifampicin (RIF) and vancomycin (VAN) in both in vitro and in vivo models.