抑制双组分信号转导系统的抗菌剂。
Antibacterial agents that inhibit two-component signal transduction systems.
作者信息
Barrett J F, Goldschmidt R M, Lawrence L E, Foleno B, Chen R, Demers J P, Johnson S, Kanojia R, Fernandez J, Bernstein J, Licata L, Donetz A, Huang S, Hlasta D J, Macielag M J, Ohemeng K, Frechette R, Frosco M B, Klaubert D H, Whiteley J M, Wang L, Hoch J A
机构信息
The R. W. Johnson Pharmaceutical Research Institute, Route 202, P.O. Box 300, Raritan, NJ 08869, USA.
出版信息
Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5317-22. doi: 10.1073/pnas.95.9.5317.
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.
已发现一类能抑制革兰氏阳性病原菌生长的抗菌剂。RWJ - 49815是一类疏水性酪胺家族的代表，它不仅是一种强效的革兰氏阳性杀菌抗菌剂，还能在体外抑制KinA::Spo0F双组分信号转导系统中激酶A的自磷酸化。RWJ - 49815的类似物在抑制细菌生长的能力上差异很大，且这种能力与其作为激酶A抑制剂的活性直接相关。与强效喹诺酮类药物环丙沙星相比，RWJ - 49815在实验室传代实验中显示出较低的耐药性出现率。抑制组氨酸蛋白激酶::反应调节因子双组分信号转导途径可能提供了一个机会，通过在单个细菌中用单一抑制剂靶向多种蛋白质来降低染色体耐药性的出现。这类抑制剂可能代表了一类抗菌剂，有可能在抗菌治疗方面取得突破。
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