Mohamed Malik Suliman, Soltane Raya, Alatwi Eid, Alasiri Ahlam, Almulla Nuha, Abdelkader Karim, Sayed Ahmed M
Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka, 72388, Al-Jouf, Kingdom of Saudi Arabia.
Department of Biology, Adham University College, Umm Al-Qura University, Makkah, 21955, Kingdom of Saudi Arabia.
Biochem Biophys Res Commun. 2025 May 5;762:151742. doi: 10.1016/j.bbrc.2025.151742. Epub 2025 Apr 3.
Pseudomonas aeruginosa is a formidable pathogen linked to various challenging infections. Quorum sensing (QS) plays a pivotal role in regulating the virulence factors of P. aeruginosa. Targeting QS represents a promising strategy for mitigating P. aeruginosa virulence. This study explores the potential of niclosamide (NIC) as an antivirulence agent, emphasizing its effects on biofilm formation, pigment production, and its molecular interaction with the QS regulator, LasR. A comprehensive methodology was employed, encompassing in-silico, molecular, and in vitro analyses to assess the antivirulence properties of NIC. Sub-inhibitory concentrations of NIC (64 μg/ml) were evaluated for their capacity to inhibit biofilm formation and pigment production in P. aeruginosa. NIC resulted in a 45.4 % reduction in biofilm formation, a 48.8 % decrease in pyocyanin production, and a 41.3 % reduction in rhamnolipid production. Furthermore, NIC displayed a dose-dependent antagonistic effect on LasR, with an IC50 of 5.82 ± 0.17 μM, without any noted agonistic activity. Molecular modeling and molecular dynamics (MD) simulations indicated that NIC interacts with LasR, hindering its dimerization and destabilizing its structure. These findings were corroborated by sedimentation velocity experiments and thermal shift assays. NIC shows considerable promise as an antivirulence agent against P. aeruginosa by disrupting the LasR-mediated QS system. Through its interaction with LasR, NIC inhibits biofilm formation and diminishes the production of critical virulence factors, making P. aeruginosa less virulent and more vulnerable to conventional antibiotics and immune responses.
铜绿假单胞菌是一种与多种具有挑战性的感染相关的强大病原体。群体感应（QS）在调节铜绿假单胞菌的毒力因子方面起着关键作用。靶向群体感应是减轻铜绿假单胞菌毒力的一种有前景的策略。本研究探讨了氯硝柳胺（NIC）作为一种抗毒力剂的潜力，重点关注其对生物膜形成、色素产生的影响以及与群体感应调节因子LasR的分子相互作用。采用了全面的方法，包括计算机模拟、分子和体外分析，以评估NIC的抗毒力特性。评估了亚抑制浓度的NIC（64μg/ml）抑制铜绿假单胞菌生物膜形成和色素产生的能力。NIC使生物膜形成减少了45.4%，绿脓菌素产生减少了48.8%，鼠李糖脂产生减少了41.3%。此外，NIC对LasR表现出剂量依赖性拮抗作用，IC50为5.82±0.17μM，未观察到任何激动活性。分子建模和分子动力学（MD）模拟表明，NIC与LasR相互作用，阻碍其二聚化并使其结构不稳定。沉降速度实验和热位移分析证实了这些发现。通过破坏LasR介导的群体感应系统，NIC作为一种抗铜绿假单胞菌毒力的药物显示出相当大的前景。通过与LasR相互作用，NIC抑制生物膜形成并减少关键毒力因子的产生，使铜绿假单胞菌的毒力降低，更容易受到传统抗生素和免疫反应的影响。
