Alyahyawy Othman Yahya, Munshi Raafat M, Badr-Eldin Shaimaa M, Aldawsari Hibah Mubarak, Abualsunun Walaa, Abbas Hisham A, Salem Ibrahim M, Hegazy Wael A H, Nazeih Shaimaa I
Department of Medical Laboratory Technology (MLT), Faculty of Applied Medical Sciences, King Abdulaziz University, 80200, Rabigh, Saudi Arabia.
Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, 21589, Jeddah, Saudi Arabia.
AMB Express. 2025 Feb 22;15(1):33. doi: 10.1186/s13568-025-01835-3.
Resistance to antibiotics is a critical growing public health problem that needs urgent action to combat. To avoid the stress on bacterial growth that evokes the development of resistance, anti-virulence agents can be an attractive strategy as they do not target bacterial growth. There are FDA approved drugs have been screened for their anti-virulence activities. Lamivudine (LAM) is a synthetic nucleoside analogue used as an antiretroviral in treatment of HIV and can be used in treatment of HBV. The present study aimed to assess the anti-virulence activities of LAM against a clinically important pathogen Pseudomonas aeruginosa. The LAM's antibiofilm and anti-virulence activities were evaluated. The impact of LAM on the quorum sensing (QS) systems which control the production of these virulence factors was assessed virtually and by quantification of the expression of QS-encoding genes. Furthermore, in vivo mice protection assay was conducted to attest the LAM's anti-pathogenic activity. The current findings elaborated the promising anti-pathogenic and anti-QS activities of LAM. LAM interfered with biofilm formation in P. aeruginosa PAO1 strain. Moreover, swarming motility and production of pyocyanin and protease were significantly diminished. At the molecular level, LAM downregulated the QS-encoding genes LasI, LasR, RhlR, PqsA and PqsR. Additionally, the detailed in silico docking and molecular simulation studies showed the considered high LAM's ability to bind and hinder the QS receptors in the P. aeruginosa. In an agreement with in vitro and in silico, the in vivo results showed the LAM full protection of mice against P. aeruginosa. In conclusion, LAM could be repurposed to be employed as adjunct therapy with traditional antibiotics for treating serious pseudomonal infections.
抗生素耐药性是一个日益严重的关键公共卫生问题，需要采取紧急行动加以应对。为避免因细菌生长压力引发耐药性的产生，抗毒力药物可能是一种有吸引力的策略，因为它们不针对细菌生长。已有经美国食品药品监督管理局（FDA）批准的药物因其抗毒力活性而接受筛选。拉米夫定（LAM）是一种合成核苷类似物，用作抗逆转录病毒药物治疗HIV，也可用于治疗HBV。本研究旨在评估拉米夫定对临床重要病原菌铜绿假单胞菌的抗毒力活性。对拉米夫定的抗生物膜和抗毒力活性进行了评估。通过虚拟评估以及对群体感应（QS）编码基因表达的定量分析，评估了拉米夫定对控制这些毒力因子产生的群体感应系统的影响。此外，还进行了体内小鼠保护试验以证明拉米夫定的抗致病活性。目前的研究结果阐述了拉米夫定有前景的抗致病和抗群体感应活性。拉米夫定干扰了铜绿假单胞菌PAO1菌株的生物膜形成。此外，群体游动性以及绿脓菌素和蛋白酶的产生均显著减少。在分子水平上，拉米夫定下调了QS编码基因LasI、LasR、RhlR、PqsA和PqsR。此外，详细的计算机对接和分子模拟研究表明，拉米夫定具有较高的结合并阻碍铜绿假单胞菌中群体感应受体的能力。与体外和计算机模拟结果一致，体内结果显示拉米夫定能使小鼠完全免受铜绿假单胞菌感染。总之，拉米夫定可重新用于与传统抗生素联合治疗严重的假单胞菌感染。
