Inhibitors of two-component signal transduction systems: Inhibition of alginate gene activation in Pseudomonas aeruginosa

Siddhartha Roychoudhury, Nicolette A. Zielinski, Alexander J. Ninfa, Norris E. Allen, Louis N. Jungheim, Thalia I. Nicas, A. M. Chakrabarty*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

82 Scopus citations

Abstract

Pseudomonas aeruginosa strains infecting cystic fibrosis patients often produce copious amounts of the exopolysaccharide alginate. Expression of alginate genes in P. aeruginosa is regulated by several proteins including members of the two-component bacterial signal transduction systems. Two of these regulatory proteins are AlgR1, the DNA-binding response regulator that transcriptionaliy activates alginate gene expression, and AlgR2, the kinase that modifies AlgR1 via phosphorylation to enhance its activity. In this paper, we report the identification of compounds that inhibit alginate gene expression by inhibiting (i) the phosphorylation/dephosphorylation of AlgR2 and (ii) the DNA-binding activity of AlgR1. Compounds with these activities may have potential as components of therapy for eliminating P. aeruginosa infection from the cystic fibrosis lung. In addition, we describe the effect of these compounds on the autophosphorylation activity of other known two-component kinases and show the ability of one compound to significantly inhibit the kinase activities of CheA, NRII, and KinA.

Original languageEnglish (US)
Pages (from-to)965-969
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume90
Issue number3
DOIs
StatePublished - Feb 1 1993

Keywords

  • Bacterial protein kinase inhibitor
  • Inhibition of DNA-protein interaction

ASJC Scopus subject areas

  • General

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