Inhibitors of bacterial cystathionine beta-lyase: leads for new antimicrobial agents and probes of enzyme structure and function

J Med Chem. 2007 Feb 22;50(4):755-64. doi: 10.1021/jm061132r.

Abstract

The biosynthesis of methionine is an attractive antibiotic target given its importance in protein and DNA metabolism and its absence in mammals. We have performed a high-throughput screen of the methionine biosynthesis enzyme cystathionine beta-lyase (CBL) against a library of 50 000 small molecules and have identified several compounds that inhibit CBL enzyme activity in vitro. These hit molecules were of two classes: those that blocked CBL activity with mixed steady-state inhibition and those that covalently interacted with the enzyme at the active site pyridoxal phosphate cofactor with slow-binding inhibition kinetics. We determined the crystal structure of one of the slow-binding inhibitors in complex with CBL and used this structure as a guide in the synthesis of a small, focused library of analogues, some of which had improved enzyme inhibition properties. These studies provide the first lead molecules for antimicrobial agents that target cystathionine beta-lyase in methionine biosynthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Anti-Infective Agents / chemical synthesis*
  • Anti-Infective Agents / chemistry
  • Anti-Infective Agents / pharmacology
  • Antifungal Agents / chemical synthesis
  • Antifungal Agents / chemistry
  • Antifungal Agents / pharmacology
  • Bacteria / enzymology*
  • Benzamides / chemical synthesis*
  • Benzamides / chemistry
  • Benzamides / pharmacology
  • Candida albicans / drug effects
  • Crystallography, X-Ray
  • Escherichia coli / enzymology
  • Hydrazines / chemical synthesis*
  • Hydrazines / chemistry
  • Hydrazines / pharmacology
  • Lyases / antagonists & inhibitors*
  • Lyases / chemistry*
  • Lyases / genetics
  • Microbial Sensitivity Tests
  • Models, Molecular*
  • Quantitative Structure-Activity Relationship*
  • Salmonella typhi / enzymology

Substances

  • Anti-Bacterial Agents
  • Anti-Infective Agents
  • Antifungal Agents
  • Benzamides
  • Hydrazines
  • Lyases
  • cystathionine beta-lyase