Acute hepatopancreatic necrosis disease (AHPND) caused by Vibrio parahaemolyticus resulted in great economic losses in global shrimp aquaculture. There is an urgent need for development of novel strategies to combat AHPND-causing V. parahaemolyticus (Vp_AHPND), given that one of the greatest challenges currently is the widespread use of antibiotics and subsequent emergence of multidrug-resistant bacteria. Here, we proposed a broad-spectrum antivirulence approach targeting a conserved histidine kinase, QseC, which has been demonstrated to activate virulence expression in several Gram-negative pathogens. Our results showed that QseC mediated the catecholamine stimulated effects on growth and flagellar motility of Vp_AHPND. Transcriptome analysis revealed that QseC was involved in the global regulation of the virulence of Vp_AHPND as the ΔqseC mutant exhibited a decreased expression of genes related to type IV pilin, flagellar motility, and biofilm formation, while an overexpression of type VI secretion system and cell wall biosynthesis. Subsequently, the bacterial catecholamine receptor antagonist LED209 not only neutralized the stimulatory effects of host catecholamines on the growth and motility of Vp_AHPNDin vitro, but also attenuated the virulence of Vp_AHPND towards brine shrimp larvae and white shrimp in vivo. Additionally, LED209 presented no interference with pathogen growth, nor the toxicity to the experimental animals. These results suggest that QseC can be an attractive antivirulence therapy target, and LED209 is a promising candidate for development of broad-spectrum antivirulence agents. This is the first study that demonstrated the role of QseC in the global regulation of Vp_AHPND infection and demonstrated the antivirulence potential of LED209, which provides insight into the use of an antivirulence approach for targeting not only Vp_AHPND, but also a much larger collection of pathogenic bacteria.

引起的急性肝胰腺坏死病（AHPND） 副溶血性弧菌在全球虾类养殖中造成了巨大的经济损失。迫切需要开发新的策略来应对AHPND致副溶血弧菌 （副总裁_AHPND），考虑到的最大的挑战之一是目前广泛使用的抗生素和耐多药细菌的后来出现。在这里，我们提出了一种针对保守的组氨酸激酶QseC的广谱抗毒力方法，该方法已被证明可以激活几种革兰氏阴性病原体中的毒力表达。我们的结果表明，QseC介导了儿茶酚胺刺激的生长和鞭毛运动。副总裁_AHPND。转录组分析表明，QseC参与了全球对毒力的调节。副总裁_AHPND作为Δ质量体系突变体表现出与IV型菌毛蛋白，鞭毛运动和生物膜形成相关的基因表达降低，而VI型分泌系统和细胞壁生物合成的过表达。随后，细菌儿茶酚胺受体拮抗剂LED209不仅中和了宿主儿茶酚胺对小鼠生长和运动的刺激作用。副总裁_AHPND体外，但也减弱了 副总裁_AHPND对盐水虾幼虫和白虾体内。另外，LED209对病原体的生长没有干扰，也没有对实验动物的毒性。这些结果表明，QseC可以成为有吸引力的抗病毒治疗靶标，而LED209是开发广谱抗病毒剂的有希望的候选者。这是第一个证明QseC在全球监管中的作用的研究副总裁_AHPND感染并证明了LED209的_抗毒潜力，这不仅为使用_{抗毒方法靶向}治疗提供了见解副总裁_AHPND，而且病原菌的收集量要大得多。