Bhalerao Sonali Eknath, Sen Himanshu, Raychaudhuri Saumya
CSIR-Institute of Microbial Technology, Chandigarh, India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
PLoS One. 2024 Dec 5;19(12):e0315052. doi: 10.1371/journal.pone.0315052. eCollection 2024.
Cholera is a dreadful disease. The scourge of this deadly disease is still evident in the developing world. Though several therapeutic strategies are in practice to combat and contain the disease, there is still a need for new drugs to control the disease safely and effectively. Keeping in view the concern, we first successfully established an inducible yeast model to express cholera toxin subunit A, and then used this yeast model, to screen a small molecule library against cholera toxin A subunit. Our effort resulted in the discovery of a small molecule, apomorphine (a Parkinson's disease drug) effective in reducing the lethality of toxic subunit in yeast model. In addition, novobiocin, an inhibitor of ADP ribosylation process, a key biochemical event through which cholera toxin exerts its action on host, was also found to rescue yeast cells from cholera toxin A subunit mediated toxicity. Finally, the effects of both molecules were tested on the cholera toxin-treated human gut epithelial cell line HT29, and it was observed that both apomorphine and novobiocin prevented cholera toxin-mediated cellular toxicity on HT29 intestinal epithelial cells.
霍乱是一种可怕的疾病。在发展中世界，这种致命疾病的祸害依然明显。尽管目前有多种治疗策略用于对抗和控制该疾病，但仍需要新的药物来安全有效地控制病情。考虑到这一关切，我们首先成功建立了一个可诱导的酵母模型来表达霍乱毒素A亚基，然后利用这个酵母模型筛选针对霍乱毒素A亚基的小分子文库。我们的努力发现了一种小分子——阿扑吗啡（一种治疗帕金森病的药物），它能有效降低酵母模型中毒性亚基的致死率。此外，新生霉素作为ADP核糖基化过程的抑制剂，而ADP核糖基化过程是霍乱毒素对宿主发挥作用的关键生化事件，也被发现可使酵母细胞从霍乱毒素A亚基介导的毒性中恢复。最后，在经霍乱毒素处理的人肠道上皮细胞系HT29上测试了这两种分子的效果，结果观察到阿扑吗啡和新生霉素均可预防霍乱毒素对HT29肠道上皮细胞的细胞毒性。
