Inhibitors of two-component signal transduction systems: inhibition of alginate gene activation in Pseudomonas aeruginosa.
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 transcriptionally 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.
Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago 60612.
S
S
Roychoudhury
N A
NA
Zielinski
A J
AJ
Ninfa
N E
NE
Allen
L N
LN
Jungheim
T I
TI
Nicas
A M
AM
Chakrabarty
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000464:Alginates / Q000378:metabolism*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects*; D005798:Genes, Bacterial; D006160:Guanosine Triphosphate / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism; D000072236:Methyl-Accepting Chemotaxis Proteins; D008957:Models, Genetic; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D015534:Trans-Activators; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation
C079502:AlgQ protein, Pseudomonas aeruginosa; D000464:Alginates; D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D000072236:Methyl-Accepting Chemotaxis Proteins; D047428:Protein Kinase Inhibitors; D015534:Trans-Activators; C075521:kinA protein, Bacillus subtilis; C067678:AlgR1 protein, Pseudomonas syringae; D006160:Guanosine Triphosphate; D000255:Adenosine Triphosphate; D011494:Protein Kinases; D010744:Phosphoric Monoester Hydrolases