Fragment-Based Drug Discovery of Inhibitors of Phosphopantetheine Adenylyltransferase from Gram-Negative Bacteria

J Med Chem. 2018 Apr 26;61(8):3309-3324. doi: 10.1021/acs.jmedchem.7b01691. Epub 2018 Apr 9.

Abstract

The discovery and development of new antibiotics capable of curing infections due to multidrug-resistant and pandrug-resistant Gram-negative bacteria are a major challenge with fundamental importance to our global healthcare system. Part of our broad program at Novartis to address this urgent, unmet need includes the search for new agents that inhibit novel bacterial targets. Here we report the discovery and hit-to-lead optimization of new inhibitors of phosphopantetheine adenylyltransferase (PPAT) from Gram-negative bacteria. Utilizing a fragment-based screening approach, we discovered a number of unique scaffolds capable of interacting with the pantetheine site of E. coli PPAT and inhibiting enzymatic activity, including triazolopyrimidinone 6. Structure-based optimization resulted in the identification of two lead compounds as selective, small molecule inhibitors of bacterial PPAT: triazolopyrimidinone 53 and azabenzimidazole 54 efficiently inhibited E. coli and P. aeruginosa PPAT and displayed modest cellular potency against the efflux-deficient E. coli Δ tolC mutant strain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / metabolism
  • Anti-Bacterial Agents / pharmacology*
  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / chemistry
  • Benzimidazoles / metabolism
  • Benzimidazoles / pharmacology
  • Binding Sites
  • Drug Discovery
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Escherichia coli / drug effects
  • Escherichia coli / enzymology
  • Escherichia coli Proteins / antagonists & inhibitors*
  • Escherichia coli Proteins / chemistry
  • Escherichia coli Proteins / metabolism
  • Heterocyclic Compounds, 2-Ring / chemical synthesis
  • Heterocyclic Compounds, 2-Ring / chemistry
  • Heterocyclic Compounds, 2-Ring / metabolism
  • Heterocyclic Compounds, 2-Ring / pharmacology*
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Nucleotidyltransferases / antagonists & inhibitors*
  • Nucleotidyltransferases / chemistry
  • Nucleotidyltransferases / metabolism
  • Protein Binding
  • Pseudomonas aeruginosa / drug effects
  • Pseudomonas aeruginosa / enzymology
  • Pyrimidinones / chemical synthesis
  • Pyrimidinones / chemistry
  • Pyrimidinones / metabolism
  • Pyrimidinones / pharmacology
  • Triazoles / chemical synthesis
  • Triazoles / chemistry
  • Triazoles / metabolism
  • Triazoles / pharmacology

Substances

  • Anti-Bacterial Agents
  • Benzimidazoles
  • Enzyme Inhibitors
  • Escherichia coli Proteins
  • Heterocyclic Compounds, 2-Ring
  • Pyrimidinones
  • Triazoles
  • Nucleotidyltransferases
  • pantetheine-phosphate adenylyltransferase