Sandala Jenna L, Eichar Bradley W, Kuo Laura G, Hahn Mark M, Basak Akash K, Huggins William M, Woolard Katherine, Melander Christian, Gunn John S
Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States of America.
Department of Microbial Infection and Immunity, The Ohio State University College of Medicine, Columbus, Ohio, United States of America.
PLoS Pathog. 2020 Dec 28;16(12):e1009192. doi: 10.1371/journal.ppat.1009192. eCollection 2020 Dec.
Asymptomatic carriage of Salmonella Typhi continues to facilitate the transmission of typhoid fever, resulting in 14 million new infections and 136,000 fatalities each year. Asymptomatic chronic carriage of S. Typhi is facilitated by the formation of biofilms on gallstones that protect the bacteria from environmental insults and immune system clearance. Here, we identified two unique small molecules capable of both inhibiting Salmonella biofilm growth and disrupting pre-formed biofilm structures without affecting bacterial viability. In a mouse model of chronic gallbladder Salmonella carriage, treatment with either compound reduced bacterial burden in the gallbladder by 1-2 logs resulting in bacterial dissemination to peripheral organs that was associated with increased mortality. Co-administration of either compound with ciprofloxacin not only enhanced compound efficacy in the gallbladder by a further 1-1.5 logs for a total of 3-4.5 log reduction, but also prevented bacterial dissemination to peripheral organs. These data suggest a dual-therapy approach targeting both biofilm and planktonic populations can be further developed as a safe and efficient treatment of biofilm-mediated chronic S. Typhi infections.
伤寒沙门氏菌的无症状携带持续推动伤寒热的传播，每年导致1400万新感染病例和13.6万人死亡。胆囊结石上生物膜的形成促进了伤寒沙门氏菌的无症状慢性携带，这种生物膜保护细菌免受环境侵害和免疫系统清除。在此，我们鉴定出两种独特的小分子，它们既能抑制沙门氏菌生物膜生长，又能破坏预先形成的生物膜结构，且不影响细菌活力。在慢性胆囊伤寒沙门氏菌携带的小鼠模型中，用任一化合物治疗可使胆囊中的细菌载量降低1至2个对数，导致细菌扩散至外周器官，这与死亡率增加相关。任一化合物与环丙沙星联合给药，不仅使化合物在胆囊中的疗效进一步提高1至1.5个对数，总共降低3至4.5个对数，还能防止细菌扩散至外周器官。这些数据表明，针对生物膜和浮游菌群体的双重治疗方法可进一步开发，作为治疗生物膜介导的慢性伤寒沙门氏菌感染的安全有效疗法。
