Antibacterial agents that inhibit two-component signal transduction systems.
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.
Barrett
J F
JF
The R. W. Johnson Pharmaceutical Research Institute, Route 202, P.O. Box 300, Raritan, NJ 08869, USA.
Goldschmidt
R M
RM
Lawrence
L E
LE
Foleno
B
B
Chen
R
R
Demers
J P
JP
Johnson
S
S
Kanojia
R
R
Fernandez
J
J
Bernstein
J
J
Licata
L
L
Donetz
A
A
Huang
S
S
Hlasta
D J
DJ
Macielag
M J
MJ
Ohemeng
K
K
Frechette
R
R
Frosco
M B
MB
Klaubert
D H
DH
Whiteley
J M
JM
Wang
L
L
Hoch
J A
JA
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*
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