Dzoyem Jean Paul, Hamamoto Hiroshi, Ngameni Barthelemy, Ngadjui Bonaventure Tchaleu, Sekimizu Kazuhisa
Laboratory of Microbiology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
Drug Discov Ther. 2013 Apr;7(2):66-72.
Naturally occurring flavonoids have been reported to possess antimicrobial activity against a wide range of pathogens. However, the antimicrobial action mechanism of these compounds has not yet been elucidated. This study investigated the mechanism underlying the antibacterial activity of four flavonoids: 6,8-diprenyleriodictyol (1), isobavachalcone (2), 6-prenylapigenin (3) and 4-hydroxylonchocarpin (4). In addition, the toxicity of these compounds was evaluated. Determination of the minimum inhibitory concentrations (MICs) was performed by microbroth dilution method. Radiolabeled thymidine, uridine, and methionine were used to evaluate the effect of the compounds on the biosynthesis of DNA, RNA, and proteins while the sensitive cyanine dye DiS-C3-(5) (3,3'-dipropylthiadicarbocyanine iodide) was used for the effect on membrane potential. Bactericidal/bacteriolysis activities were performed by time-kill kinetic method. In the toxicity study, the numbers of survivors was recorded after injection of compounds into the hemolymph of silkworm larvae. Compounds showed significant antibacterial activity against Staphylococcus aureus including methicillin-resistant S. aureus (MRSA) strains with MICs values ranged between 0.5-128 μg/mL. Depolarization of membrane and inhibition of DNA, RNA, and proteins synthesis were observed in S. aureus when treated with those flavonoids. At 5-fold minimum inhibitory concentration, compounds reduced rapidly the bacterial cell density and caused lysis of S. aureus. Compounds 1, 2, and 4 did not show obvious toxic effects in silkworm larvae up to 625 μg/g of body weight. Flavonoids from Dorstenia species, 6,8-diprenyleriodictyol, isobavachalcone, and 4-hydroxylonchocarpin are bactericidal compounds. They cause damage of cell membrane, leading to the inhibition of macromolecular synthesis. Taking into account the in vivo safety and their significant antimicrobial potency, these flavonoids are promising leads for further drug development.
据报道，天然存在的黄酮类化合物对多种病原体具有抗菌活性。然而，这些化合物的抗菌作用机制尚未阐明。本研究调查了四种黄酮类化合物：6,8-二异戊烯基圣草酚（1）、异补骨脂查尔酮（2）、6-异戊烯基芹菜素（3）和4-羟基轮叶戟素（4）的抗菌活性机制。此外，还评估了这些化合物的毒性。通过微量肉汤稀释法测定最低抑菌浓度（MICs）。使用放射性标记的胸腺嘧啶核苷、尿嘧啶核苷和甲硫氨酸来评估化合物对DNA、RNA和蛋白质生物合成的影响，同时使用灵敏的花菁染料DiS-C3-(5)（3,3'-二丙基硫代二碳菁碘化物）来评估对膜电位的影响。通过时间杀灭动力学方法进行杀菌/溶菌活性测定。在毒性研究中，将化合物注射到家蚕幼虫血淋巴后记录存活数量。这些化合物对金黄色葡萄球菌包括耐甲氧西林金黄色葡萄球菌（MRSA）菌株显示出显著的抗菌活性，MICs值在0.5-128μg/mL之间。用这些黄酮类化合物处理金黄色葡萄球菌时，观察到膜去极化以及DNA、RNA和蛋白质合成受到抑制。在5倍最低抑菌浓度下，这些化合物迅速降低细菌细胞密度并导致金黄色葡萄球菌裂解。化合物1、2和4在高达625μg/g体重的家蚕幼虫中未显示明显的毒性作用。来自多蕊麻属植物的黄酮类化合物6,8-二异戊烯基圣草酚、异补骨脂查尔酮和4-羟基轮叶戟素是杀菌化合物。它们会导致细胞膜损伤，从而抑制大分子合成。考虑到其体内安全性及其显著的抗菌效力，这些黄酮类化合物是进一步药物开发的有前景的先导化合物。
