April 21, 2020  |  

Potent LpxC Inhibitors with In Vitro Activity Against Multi-Drug Resistant Pseudomonas aeruginosa.

Authors: Krause, Kevin M and Haglund, Cat M and Hebner, Christy and Serio, Alisa W and Lee, Grace and Nieto, Vincent and Cohen, Frederick and Kane, Timothy R and Machajewski, Timothy D and Hildebrandt, Darrin and Pillar, Chris and Thwaites, Mary and Hall, Danielle and Miesel, Lynn and Hackel, Meredith and Burek, Amanda and Andrews, Logan D and Armstrong, Eliana and Swem, Lee and Jubb, Adrian and Cirz, Ryan T

New drugs with novel mechanisms of resistance are desperately needed to address both community and nosocomial infections due to Gram-negative bacteria. One such potential target is LpxC, an essential enzyme that catalyzes the first committed step of Lipid A biosynthesis. Achaogen conducted an extensive research campaign to discover novel LpxC inhibitors with activity against Pseudomonas aeruginosa We report here the in vitro antibacterial activity and pharmacodynamics of ACHN-975, the only molecule from these efforts and the first ever LpxC inhibitor to be evaluated in Phase 1 clinical trials. In addition, we describe the profile of three additional LpxC inhibitors that were identified as potential lead molecules. These efforts did not produce an additional development candidate with a sufficiently large therapeutic window and the program was subsequently terminated.Copyright © 2019 American Society for Microbiology.

Journal: Antimicrobial agents and chemotherapy
DOI: 10.1128/AAC.00977-19
Year: 2019

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