Developing inhibitors to selectively target two-component and phosphorelay signal transduction systems of pathogenic microorganisms

Curr Med Chem. 2004 Mar;11(6):765-73. doi: 10.2174/0929867043455765.

Abstract

Two-component signal transduction systems and their expanded variants known as phosphorelays are integral elements of the virulence and antimicrobial resistance responses of a wide range of pathogenic bacteria and fungi and also regulate essential functions. As a consequence, two-component systems and phosphorelays are recognized targets for the development of novel antimicrobial agents and a number of chemically synthesized inhibitors from different chemical classes have been identified by compound library screens. However, in the majority of cases these compounds do not appear to be selective for signal transduction pathways and exert their effect by multiple mechanisms of action. The key to designing molecules to selectively disrupt signal transduction may lie with the conserved features of response regulators and the structural analysis of complexes of signaling proteins.

Publication types

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

MeSH terms

  • Anti-Infective Agents* / chemistry
  • Anti-Infective Agents* / pharmacology
  • Drug Design*
  • Drug Resistance, Microbial / physiology
  • Enzyme Inhibitors* / chemistry
  • Enzyme Inhibitors* / pharmacology
  • Histidine Kinase
  • Models, Molecular
  • Molecular Structure
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors
  • Protein Kinases*
  • Signal Transduction / drug effects*
  • Virulence

Substances

  • Anti-Infective Agents
  • Enzyme Inhibitors
  • Protein Kinase Inhibitors
  • Protein Kinases
  • Histidine Kinase