Mechanistic analysis of flavonoids on bacterial virulence

性状（由申请方提供）：黄酮类化合物是膳食补充剂和草药的主要成分，据报道具有抗人类微生物感染的保护活性。然而，这些植物衍生的天然产物减轻微生物感染的确切机制尚不清楚。利用高通量筛选革兰氏阴性细菌病原体中的III型蛋白分泌，我们发现不干扰细菌生长的药用植物中的特异性黄酮类化合物可以有效拮抗这一关键的细菌毒力途径，防止鼠伤寒沙门氏菌入侵宿主细胞。为了确定特定的类黄酮如何拮抗III型分泌系统（T3SS）并减弱细菌毒力，本申请将1）开发更有效的类黄酮类似物，2）确定类黄酮T3SS抑制剂的作用机制，以及3）分析S.鼠伤寒感染由于许多革兰氏阴性细菌病原体使用III型蛋白质分泌系统感染宿主细胞，阐明类黄酮抑制细菌毒力的机制应该揭示新的靶标和先导化合物，可用于选择性靶向病原菌并保护有益的宿主微生物群。鉴于新的和耐药性细菌病原体的出现，我们的研究应该提供新的抗感染药物对抗人类的细菌感染。

DESCRIPTION (provided by applicant): Flavonoids are major components of dietary supplements and herbal medicines with reported protective activities against microbial infections in humans. However, the precise mechanisms by which these plant derived natural products attenuate microbial infections are unclear. Using a high-throughput screen for type III protein secretion in Gram-negative bacterial pathogens, we discovered specific flavonoids from medicinal plants that do not interfere with bacterial growth can effectively antagonize this key bacterial virulence pathway and prevent Salmonella typhimurium invasion of host cells. To determine how specific flavonoids can antagonize type III secretion systems (T3SSs) and attenuate bacterial virulence, this application will 1) develop more potent flavonoid analogs, 2) determine flavonoid T3SS inhibitor mechanism of action and 3) analyze more active flavonoids in cellular and animals of S. typhimurium infection. As many Gram-negative bacterial pathogens use type III protein secretion systems to infection host cells, elucidating the mechanisms by which flavonoids inhibit bacterial virulence should reveal new targets and lead compounds that could be used to selectively target pathogenic bacteria and preserve beneficial host microbiota. Given the emergence of new and antibiotic-resistant bacterial pathogens, our studies should afford new anti-infective agents combat bacterial infections in humans.