Open AccessAntibacterial agents that inhibit two-component signal transduction systems
Author(s) -
John Barrett,
Raúl Goldschmidt,
Laura Lawrence,
Barbara D. Foleno,
R. Chen,
James P. Demers,
Steven M. Johnson,
Ramesh M. Kanojia,
José A. Fernández,
Jeffrey I. Bernstein,
Lisa Licata,
A. Donetz,
Shaoming Huang,
Dennis J. Hlasta,
Mark J. Macielag,
Kwasi A. Ohemeng,
R. F. Frechette,
M. B. Frosco,
Dieter H. Klaubert,
John M. Whiteley,
L. Wang,
James A. Hoch
Publication year - 1998
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.95.9.5317
Subject(s) - autophosphorylation , histidine kinase , response regulator , signal transduction , bacteria , biology , two component regulatory system , transduction (biophysics) , antibacterial agent , kinase , microbiology and biotechnology , protein kinase a , gram negative bacteria , biochemistry , histidine , escherichia coli , enzyme , genetics , bacterial protein , gene , mutant
A class of antibacterials has been discovered that inhibits the growth of Gram-positive pathogenic bacteria. RWJ-49815, a representative of a family of hydrophobic tyramines, in addition to being a potent bactericidal Gram-positive antibacterial, inhibits the autophosphorylation of kinase A of the KinA∷Spo0F two-component signal transduction systemin vitro . Analogs of RWJ-49815 vary greatly in their ability to inhibit growth of bacteria and this ability correlates directly with their activity as kinase A inhibitors. Compared with the potent quinolone, ciprofloxacin, RWJ-49815 exhibits reduced resistance emergence in a laboratory passage experiment. Inhibition of the histidine protein kinase∷response regulator two-component signal transduction pathways may present an opportunity to depress chromosomal resistance emergence by targeting multiple proteins with a single inhibitor in a single bacterium. Such inhibitors may represent a class of antibacterials that potentially may represent a breakthrough in antibacterial therapy.