School of Pharmaceutical Sciences, Shandong University of Traditional Chinese Medicine, Jinan 250355, China; Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
School of Pharmaceutical Sciences, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.
Biochem Biophys Res Commun. 2014 Jul 11;449(4):455-9. doi: 10.1016/j.bbrc.2014.05.044. Epub 2014 May 20.
Natural small-molecule products are promising lead compounds for developing a generation of novel antimicrobials agents to meet the challenge of antibiotic-resistant pathogens. To facilitate the search for novel anti-virulence agents, we chose a virulence factor of Type Three Secretion System (T3SS) as a drug target to screen candidates from a small-molecule library in our laboratory. This study demonstrated fusaric acid had dramatically inhibitory effects on secretion of Salmonella island 1 (SPI-1) effector proteins and invasion of Salmonella into HeLa cells. Moreover, fusaric acid had no inhibitory effects on bacterial growth and viability of host cells. Protein HilA is a key regulator of SPI-1 in Salmonella, which affects transcription of SPI-1 effectors and SPI-1 apparatus genes. In this study, fusaric acid (FA) did not affect secretion of SPI-1 effectors in HilA over-expressed strain, suggesting it did not affect the transcription of SPI-1. In addition, fusaric acid did not affect the protein level of apparatus protein PrgH in SPI-1 needle complex. As a result, we proposed fusaric acid had an inhibitory effect on SPI-1 probably depending on its influence on SicA/InvF. In summary, fusaric acid is a novel inhibitor of T3SS with potential for further developing novel anti-virulence agents.
天然小分子产物是开发新一代新型抗菌药物的有前途的先导化合物，以应对抗药性病原体的挑战。为了便于寻找新型的抗毒剂，我们选择了 III 型分泌系统（T3SS）的一种毒力因子作为药物靶点，从我们实验室的小分子文库中筛选候选物。这项研究表明，呋塞米酸对沙门氏菌岛 1（SPI-1）效应蛋白的分泌和沙门氏菌侵入 HeLa 细胞具有显著的抑制作用。此外，呋塞米酸对细菌生长和宿主细胞活力没有抑制作用。蛋白 HilA 是沙门氏菌 SPI-1 的关键调节因子，它影响 SPI-1 效应子和 SPI-1 装置基因的转录。在这项研究中，呋塞米酸（FA）在 HilA 过表达菌株中不影响 SPI-1 效应子的分泌，这表明它不影响 SPI-1 的转录。此外，呋塞米酸不影响 SPI-1 针复合物中装置蛋白 PrgH 的蛋白水平。因此，我们提出呋塞米酸对 SPI-1 的抑制作用可能取决于其对 SicA/InvF 的影响。总之，呋塞米酸是一种新型的 T3SS 抑制剂，具有进一步开发新型抗毒剂的潜力。
