Potent LpxC Inhibitors with In Vitro Activity against Multidrug-Resistant Pseudomonas aeruginosa

  • Antimicrob Agents Chemother. 2019 Oct 22;63(11):e00977-19. doi: 10.1128/AAC.00977-19.
Kevin M Krause  1 ,  Cat M Haglund  2 ,  Christy Hebner  2 ,  Alisa W Serio  2 ,  Grace Lee  2 ,  Vincent Nieto  2 ,  Frederick Cohen  2 ,  Timothy R Kane  2 ,  Timothy D Machajewski  2 ,  Darrin Hildebrandt  2 ,  Chris Pillar  3 ,  Mary Thwaites  3 ,  Danielle Hall  3 ,  Lynn Miesel  4 ,  Meredith Hackel  5 ,  Amanda Burek  2 ,  Logan D Andrews  2 ,  Eliana Armstrong  2 ,  Lee Swem  2 ,  Adrian Jubb  2 ,  Ryan T Cirz  2
Affiliations
  • 1. Achaogen Inc., South San Francisco, California, USA [email protected].
  • 2. Achaogen Inc., South San Francisco, California, USA.
  • 3. Micromyx, Inc., Kalamazoo, Michigan, USA.
  • 4. Pharmacology Discovery Services, Ltd., New Taipei City, Taiwan.
  • 5. International Health Management Associates, Inc., Schaumburg, Illinois, USA.
PMID: 31451507 DOI: 10.1128/AAC.00977-19
Abstract

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 profiles 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.

Keywords
LpxC; Pseudomonas aeruginosa.
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