Mechanistic analysis of flavonoids on bacterial virulence

描述（由申请人提供）：黄酮类化合物是膳食补充剂和草药的主要成分，据报道对人类微生物感染具有保护作用。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。通过对革兰氏阴性病原菌III型蛋白分泌的高通量筛选，我们发现药用植物中不干扰细菌生长的黄酮类化合物可以有效拮抗这一关键的细菌毒力通路，阻止鼠伤寒沙门菌入侵宿主细胞。为了确定特定的黄酮类化合物如何拮抗III型分泌系统（T3SS）并减弱细菌毒力，本应用程序将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，3)分析鼠伤寒沙门氏菌感染细胞和动物中的更多活性黄酮类化合物。由于许多革兰氏阴性细菌病原体利用III型蛋白分泌系统感染宿主细胞，阐明黄酮类化合物抑制细菌毒力的机制将揭示新的靶点和先导化合物，这些靶点和先导化合物可用于选择性地靶向致病菌并保护有益的宿主微生物群。鉴于新的和耐抗生素的细菌病原体的出现，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.