Flavonoid inhibitors as novel antimycobacterial agents targeting Rv0636, a putative dehydratase enzyme involved in Mycobacterium tuberculosis fatty acid synthase II
Flavonoid inhibitors as novel antimycobacterial agents targeting Rv0636, a putative dehydratase enzyme involved in Mycobacterium tuberculosis fatty acid synthase II
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DOI：
10.1099/mic.0.2007/009936-0
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发表时间：
2007-10-01
期刊：
影响因子：
2.8
通讯作者：
Besra, Gurdyal S.
中科院分区：
文献类型：
--
作者：
Brown, Alistair K.;Papaemmanouil, Athina;Besra, Gurdyal S.
黄酮类化合物是一类具有生物活性的多酚类植物次生代谢产物。其中几种具有针对大肠杆菌和恶性疟原虫的有效体内活性，靶向参与脂肪酸生物合成的酶，如烯酰基-ACP-还原酶、β-酮酰基-ACP还原酶和β-羟酰基-ACP还原酶。在此，我们报告了Butein，isoliquirtigenin，2，2 '，4'-trihydroxychalcone和fisetin抑制牛分枝杆菌BCG的生长。此外，在体外抑制产分枝杆菌酸的脂肪酸合成酶II（FAS-II）的耻垢分枝杆菌表明，在大肠杆菌和恶性疟原虫中观察到的相关的行动模式。通过生物信息学方法，我们已经确定Rv 0636的产物作为未知分枝杆菌淀粉酶的候选物，并且其在M. Bovis BCG能抵抗Butein和Isoliquirtigenin的生长抑制作用，并能解除体内脂肪酸和分枝菌酸生物合成的抑制。此外，在M.在体外试验中，FAS-II对这些抑制剂的敏感性较低。总的来说，数据表明这些类黄酮是分枝杆菌FAS-II的抑制剂，特别是Rv 0636，其代表分枝杆菌β-羟酰基-ACP脱氢酶的强有力的候选物。结核病FAS-II。
Flavonoids comprise a large group of bioactive polyphenolic plant secondary metabolites. Several of these possess potent in vivo activity against Escherichia coli and Plasmodium falciparum, targeting enzymes involved in fatty acid biosynthesis, such as enoyl-ACP-reductase, beta-ketoacyl-ACP reductase and beta-hydroxyacyl-ACP dehydratase. Herein, we report that butein, isoliquirtigenin, 2,2',4'-trihydroxychalcone and fisetin inhibit the growth of Mycobacterium bovis BCG. Furthermore, in vitro inhibition of the mycolic-acid-producing fatty acid synthase II (FAS-II) of Mycobacterium smegmatis suggests a mode of action related to those observed in E coli and P. falciparum. Through a bioinformatic approach, we have established the product of Rv0636 as a candidate for the unknown mycobacterial dehydratase, and its overexpression in M. bovis BCG conferred resistance to growth inhibition by butein and isoliquirtigenin, and relieved inhibition of fatty acid and mycolic acid biosynthesis in vivo. Furthermore, after overexpression of Rv0636 in M. smegmatis, FAS-II was less sensitive to these inhibitors in vitro. Overall, the data suggest that these flavonoids are inhibitors of mycobacterial FAS-II and in particular Rv0636, which represents a strong candidate for the beta-hydroxyacyl-ACP dehydratase enzyme of M. tuberculosis FAS-II.