Mechanistic analysis of flavonoids on bacterial virulence

说明(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，据报道具有预防人类微生物感染的活性。然而，这些植物提取的天然产物减轻微生物感染的确切机制尚不清楚。通过对革兰氏阴性细菌病原菌分泌III型蛋白的高通量筛选，我们发现从药用植物中提取的不干扰细菌生长的特定黄酮类化合物可以有效地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。为了确定特定的黄酮类化合物如何拮抗III型分泌系统(T3SS)和减轻细菌毒力，这一应用将1)开发更有效的黄酮类类似物，2)确定黄酮类T3SS抑制剂的作用机制，3)分析感染鼠伤寒沙门氏菌的细胞和动物中更具活性的黄酮类化合物。由于许多革兰氏阴性细菌利用III型蛋白分泌系统感染宿主细胞，阐明类黄酮抑制细菌毒力的机制将揭示新的靶点和先导化合物，可用于选择性地靶向致病菌和保存有益的宿主微生物群。鉴于新的抗药性细菌病原体的出现，我们的研究应该能够提供新的抗感染药物来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.