title: Antibacterial agents that inhibit two-component signal transduction systems.
abstract: 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 system in 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.
authors.affiliation: The R. W. Johnson Pharmaceutical Research Institute, Route 202, P.O. Box 300, Raritan, NJ 08869, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: Barrett
authors.forename: R M
authors.initials: RM
authors.lastname: Goldschmidt
authors.forename: L E
authors.initials: LE
authors.lastname: Lawrence
authors.forename: B
authors.initials: B
authors.lastname: Foleno
authors.forename: R
authors.initials: R
authors.lastname: Chen
authors.forename: J P
authors.initials: JP
authors.lastname: Demers
authors.forename: S
authors.initials: S
authors.lastname: Johnson
authors.forename: R
authors.initials: R
authors.lastname: Kanojia
authors.forename: J
authors.initials: J
authors.lastname: Fernandez
authors.forename: J
authors.initials: J
authors.lastname: Bernstein
authors.forename: L
authors.initials: L
authors.lastname: Licata
authors.forename: A
authors.initials: A
authors.lastname: Donetz
authors.forename: S
authors.initials: S
authors.lastname: Huang
authors.forename: D J
authors.initials: DJ
authors.lastname: Hlasta
authors.forename: M J
authors.initials: MJ
authors.lastname: Macielag
authors.forename: K
authors.initials: K
authors.lastname: Ohemeng
authors.forename: R
authors.initials: R
authors.lastname: Frechette
authors.forename: M B
authors.initials: MB
authors.lastname: Frosco
authors.forename: D H
authors.initials: DH
authors.lastname: Klaubert
authors.forename: J M
authors.initials: JM
authors.lastname: Whiteley
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: J A
authors.initials: JA
authors.lastname: Hoch
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004352:Drug Resistance, Microbial; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D006146:Guanidines / Q000494:pharmacology*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014320:Triphenylmethyl Compounds / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D006146:Guanidines; C112247:RWJ 49815; D014320:Triphenylmethyl Compounds; C075521:kinA protein, Bacillus subtilis; D011494:Protein Kinases