Chen D Z, Patel D V, Hackbarth C J, Wang W, Dreyer G, Young D C, Margolis P S, Wu C, Ni Z J, Trias J, White R J, Yuan Z
Versicor, Inc., Fremont, California 94555, USA.
Biochemistry. 2000 Feb 15;39(6):1256-62. doi: 10.1021/bi992245y.
Peptide deformylase (PDF) is essential in prokaryotes and absent in mammalian cells, thus making it an attractive target for the discovery of novel antibiotics. We have identified actinonin, a naturally occurring antibacterial agent, as a potent PDF inhibitor. The dissociation constant for this compound was 0.3 x 10(-)(9) M against Ni-PDF from Escherichia coli; the PDF from Staphylococcus aureus gave a similar value. Microbiological evaluation revealed that actinonin is a bacteriostatic agent with activity against Gram-positive and fastidious Gram-negative microorganisms. The PDF gene, def, was placed under control of P(BAD) in E. coli tolC, permitting regulation of PDF expression levels in the cell by varying the external arabinose concentration. The susceptibility of this strain to actinonin increases with decreased levels of PDF expression, indicating that actinonin inhibits bacterial growth by targeting this enzyme. Actinonin provides an excellent starting point from which to derive a more potent PDF inhibitor that has a broader spectrum of antibacterial activity.
肽脱甲酰基酶（PDF）在原核生物中至关重要，而在哺乳动物细胞中不存在，因此使其成为发现新型抗生素的一个有吸引力的靶点。我们已鉴定出放线诺宁，一种天然存在的抗菌剂，作为一种有效的PDF抑制剂。该化合物对来自大肠杆菌的镍-PDF的解离常数为0.3×10⁻⁹ M；来自金黄色葡萄球菌的PDF给出了类似的值。微生物学评估表明，放线诺宁是一种对革兰氏阳性和苛求革兰氏阴性微生物有活性的抑菌剂。PDF基因def在大肠杆菌tolC中置于P（BAD）的控制之下，通过改变外部阿拉伯糖浓度可调节细胞中PDF的表达水平。该菌株对放线诺宁的敏感性随PDF表达水平的降低而增加，表明放线诺宁通过靶向这种酶来抑制细菌生长。放线诺宁为衍生出具有更广泛抗菌活性谱的更有效的PDF抑制剂提供了一个极好的起点。
