Yuan Yang, Yang Xiting, Zeng Qianglin, Li Heyue, Fu Ruyi, Du Lianming, Liu Wei, Zhang Yamei, Zhou Xikun, Chu Yiwen, Zhang Xiuyue, Zhao Kelei
Key Laboratory of Bio-resources and Eco-environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, Sichuan, China.
Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, School of Pharmacy, Affiliated Hospital/Clinical College of Chengdu University, Chengdu, Sichuan, China.
Front Microbiol. 2022 Aug 15;13:978502. doi: 10.3389/fmicb.2022.978502. eCollection 2022.
relies on its complex cellular regulatory network to produce a series of virulence factors and to cause various acute and chronic infections in a wide range of hosts. Compared with traditional antibiotics which frequently accompany with widespread antibiotic resistance, crippling the virulence system of bacteria is expected to be a promising anti-infective strategy. In this study, Dimetridazole and Ribavirin, which had poor antibacterial activities on reference isolate PAO1 in nutrient medium but significantly inhibited the growth of PAO1 in M9-adenosine, were selected from 40 marketed compounds with similar core structure (furan, benzofuran, or flavonoids) to the acyl-homoserine lactone signals of quorum sensing (QS) system. The production of QS-controlled proteases, pyocyanin, and biofilm formation of PAO1 and the clinical isolates were significantly decreased by the presence of Dimetridazole or Ribavirin. Correspondingly, the majority of QS-activated genes in , including the key regulatory genes , , and and their downstream genes, were significantly inhibited by Ribavirin or Dimetridazole, as determined by RNA-sequencing and quantitative PCR. Furthermore, the susceptibilities of drug-resistant isolates to polymyxin B, meropenem, and kanamycin were remarkably promoted by the synergistic application of Dimetridazole or Ribavirin. Finally, the treatment of Ribavirin or Dimetridazole effectively protected and mice from infection. In conclusion, this study reports the antivirulence potentials of Dimetridazole and Ribavirin on and provides structural basis and methodological reference for the development of anti-pseudomonal drugs.
它依靠其复杂的细胞调节网络产生一系列毒力因子，并在广泛的宿主中引起各种急性和慢性感染。与经常伴随着广泛抗生素耐药性的传统抗生素相比，削弱细菌的毒力系统有望成为一种有前途的抗感染策略。在这项研究中，从40种具有与群体感应（QS）系统的酰基高丝氨酸内酯信号相似核心结构（呋喃、苯并呋喃或黄酮类）的市售化合物中筛选出二甲基硝唑和利巴韦林，它们在营养培养基中对参考菌株PAO1的抗菌活性较差，但在M9-腺苷中能显著抑制PAO1的生长。二甲基硝唑或利巴韦林的存在显著降低了PAO1和临床分离株中QS控制的蛋白酶、绿脓菌素的产生以及生物膜的形成。相应地，通过RNA测序和定量PCR测定，利巴韦林或二甲基硝唑显著抑制了PAO1中大多数QS激活基因，包括关键调控基因lasI、rhlI和pqsA及其下游基因。此外，二甲基硝唑或利巴韦林的协同应用显著提高了耐药分离株对多粘菌素B、美罗培南和卡那霉素的敏感性。最后，利巴韦林或二甲基硝唑的治疗有效地保护了秀丽隐杆线虫和小鼠免受铜绿假单胞菌感染。总之，本研究报道了二甲基硝唑和利巴韦林对铜绿假单胞菌的抗毒力潜力，并为抗铜绿假单胞菌药物的开发提供了结构基础和方法学参考。
