The mechanism of action of inhibitors of bacterial two-component signal transduction systems.
Two-component signal transduction systems allow bacteria to sense and respond rapidly to changes in their environment leading to specific gene activation or repression. These two-component systems are integral in the ability of pathogenic bacteria to mount and establish a successful infection within the host and, consequently, have been recognized as targets for new anti-microbial agents. In this paper, we define the site and mechanism of action of several previously identified inhibitors of bacterial two-component systems. We show that the most potent inhibitors target the carboxyl-terminal catalytic domain of the sensor kinase and exert their affect by causing structural alterations of the kinase leading to aggregation. Recognition of this phenomenon has important implications for the development of novel inhibitors of two-component systems and should facilitate the rapid identification and elimination of compounds with nonspecific affects from medicinal chemistry drug discovery programs.
Stephenson
K
K
Division of Cellular Biology, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.
Yamaguchi
Y
Y
Hoch
J A
JA
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000187:drug effects / Q000502:physiology*; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D015242:Ofloxacin / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism; D012458:Salicylanilides / Q000494:pharmacology; D015290:Second Messenger Systems / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D014320:Triphenylmethyl Compounds / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D006146:Guanidines; C112247:RWJ 49815; D012458:Salicylanilides; C080951:Spo0F protein, Bacillus subtilis; D014320:Triphenylmethyl Compounds; C075521:kinA protein, Bacillus subtilis; D015242:Ofloxacin; D011494:Protein Kinases; C023342:closantel; C003390:3,3',4',5-tetrachlorosalicylanilide