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. Print 2019 Nov.

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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Bacterial Proteins / antagonists & inhibitors*
  • Catalysis / drug effects
  • Drug Resistance, Multiple, Bacterial / drug effects*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Pseudomonas aeruginosa / drug effects*
  • Pseudomonas aeruginosa / metabolism

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Enzyme Inhibitors