Inhibitory effect of the natural product betulin and its derivatives against the intracellular bacterium Chlamydia pneumoniae
Inhibitory effect of the natural product betulin and its derivatives against the intracellular bacterium Chlamydia pneumoniae
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DOI：
10.1016/j.bcp.2010.06.051
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发表时间：
2010-10-15
影响因子：
5.8
通讯作者：
Vuorela, Pia
中科院分区：
文献类型：
--
作者：
Salin, Olli;Alakurtti, Sami;Vuorela, Pia
肺炎衣原体是一种普遍的病原体，已被证明在哮喘、动脉粥样硬化和肺癌的发展中起作用。用目前使用的抗生素完全根除这种细胞内细菌实际上是不可能的，而且对新的抗衣原体化合物的研究具有挑战性，因为衣原体研究缺乏对这种细菌进行基因改造所需的工具。桦木素是一种从植物中提取的天然羽扇烷类三萜，具有多种生物活性。因此，该化合物群具有广泛的医学潜力，事实上已被证明对细胞内病原体有活性。因此，本研究选择白桦脂素及其衍生物对肺炎原体进行抑菌试验。采用体外急性感染模型，测定了32种白桦素衍生物对肺炎梭菌的抗感染作用。鉴定出5个具有潜在先导化合物特征的化合物。化合物24（白桦二肟）对菌株CWL-029的最小抑制浓度（MIC）为1 μ M，在纳米摩尔浓度下显示出活性，在290 nM处达到50%的抑制作用。用临床分离物CV-6证实了24的抗衣原体作用，其MIC为2.2 μ M.以往对白桦林及其衍生物的研究尚未发现对革兰氏阴性菌生长有如此显著的抑制作用。此外，我们还证明了这种抗衣原体活性不是由于白桦素衍生物引起的PLA(2) （EC 3.1.1.4）抑制。(C) 2010爱思唯尔公司版权所有。
Chlamydia pneumoniae is a universal pathogen that has been indicated to play a part in the development of asthma, atherosclerosis and lung cancer. The complete eradication of this intracellular bacterium is in practice impossible with the antibiotics that are currently in use and studies on new antichlamydial compounds is challenging because Chlamydia research lacks the tools required for the genetic modification of this bacterium. Betulin is a natural lupane-class triterpene derived from plants with a wide variety of biological activities. This compound group thus has wide medical potentials, and in fact has been shown to be active against intracellular pathogens. For this reason, betulin and its derivatives were selected to be assayed against C. pneumoniae in the present study.Thirty-two betulin derivatives were assayed against C. pneumoniae using an acute infection model in vitro. Five promising compounds with potential lead compound characteristics were identified. Compound 24 (betulin dioxime) gave a minimal inhibitory concentration (MIC) of 1 mu M against strain CWL-029 and showed activity in nanomolar concentrations, as 50% inhibition was achieved at 290 nM. The antichlamydial effect of 24 was confirmed with a clinical isolate CV-6, showing a MIC of 2.2 mu M. Previous research on betulin and its derivatives has not identified such a remarkable inhibition of Gram-negative bacterial growth. Furthermore, we also demonstrated that this antichlamydial activity was not due to PLA(2) (EC 3.1.1.4) inhibition caused by the betulin derivatives. (C) 2010 Elsevier Inc. All rights reserved.