Zheng Chang Ji, Sohn Mi-Jin, Lee Sangku, Hong Young-Soo, Kwak Jin-Hwan, Kim Won-Gon
Korea Research Institute of Bioscience and Biotechnology, Yusong, Daejeon 305-806, Republic of Korea.
Biochem Biophys Res Commun. 2007 Nov 3;362(4):1107-12. doi: 10.1016/j.bbrc.2007.08.144. Epub 2007 Aug 31.
Microorganisms produce many kinds of antibiotics which function in an antagonistic capacity in nature where they have much competition. Bacterial enoyl-acyl carrier protein (ACP) reductase (FabI) has been demonstrated to be an antibacterial target. However, no FabI-directed antibiotic of microbial origin has been reported so far. In this study, we found that cephalochromin with a naphtho-gamma-pyrone skeleton, a fungal secondary metabolite, inhibited FabI of Staphylococcus aureus and Escherichia coli with IC50 of 1.9 and 1.8 microM, respectively. The methylether derivatives of cephalochromin, however, did not inhibit FabI. The FabI-inhibitory activities of cephalochromin and its derivatives well correlated with antibacterial activity as well as the inhibition of cellular fatty acid biosynthesis. Furthermore, FabI-overexpressing S. aureus exhibited reduced susceptibility to cephalochromin compared to the wild-type strain, demonstrating that the mode of antibacterial action of cephalochromin is via the inhibition of FabI. These results indicate that cephalochromin is the first FabI-directed antibacterial of microbial origin and may have the potential for further antibacterial development.
微生物产生多种抗生素，在竞争激烈的自然环境中，这些抗生素发挥着拮抗作用。细菌烯酰-酰基载体蛋白（ACP）还原酶（FabI）已被证明是一个抗菌靶点。然而，迄今为止，尚未有源自微生物的针对FabI的抗生素报道。在本研究中，我们发现具有萘并-γ-吡喃酮骨架的真菌次级代谢产物头孢色菌素，对金黄色葡萄球菌和大肠杆菌的FabI具有抑制作用，其IC50分别为1.9和1.8微摩尔。然而，头孢色菌素的甲基醚衍生物并不抑制FabI。头孢色菌素及其衍生物对FabI的抑制活性与抗菌活性以及对细胞脂肪酸生物合成的抑制作用密切相关。此外，与野生型菌株相比，过表达FabI的金黄色葡萄球菌对头孢色菌素的敏感性降低，这表明头孢色菌素的抗菌作用方式是通过抑制FabI。这些结果表明，头孢色菌素是首个源自微生物的针对FabI的抗菌剂，可能具有进一步抗菌开发的潜力。
