Ren, Huan, Liu, Yiwei, Zhou, Jingyi, Long, Yuqing, Liu, Chang, Xia, Bin, Shi, Jing, Fan, Zheng, Liang, Yuying, Chen, Shuiping, Xu, Jun, Wang, Penghua, Zhang, Yanhong, Zhu, Guangbo, Liu, Huimin, Jin, Yongxin, Bai, Fang, Cheng, Zhihui, Jin, Shouguang, and Wu, Weihui
Background: Trans-translation is a ribosome rescue system that plays an important role in bacterial tolerance to environmental stresses. It is absent in animals, making it a potential treatment target. However, its role in antibiotic tolerance in Pseudomonas aeruginosa remains unknown.Methods: The role and activity of trans-translation during antibiotic treatment were examined with a trans-translation-deficient strain and a genetically modified trans-translation component gene, respectively. In vitro assays and murine infection models were used to examine the effects of suppression of trans-translation.Results: We found that the trans-translation system plays an essential role in P. aeruginosa tolerance to azithromycin and multiple aminoglycoside antibiotics. We further demonstrated that gentamicin could suppress the azithromycin-induced activation of trans-translation. Compared with each antibiotic individually, gentamicin and azithromycin combined increased the killing efficacy against planktonic and biofilm-associated P. aeruginosa cells, including a reference strain PA14 and its isogenic carbapenem-resistance oprD mutant, the mucoid strain FRD1, and multiple clinical isolates. Furthermore, the gentamicin-azithromycin resulted in improved bacterial clearance in murine acute pneumonia, biofilm implant, and cutaneous abscess infection models.Conclusions: Combination treatment with gentamicin and azithromycin is a promising strategy in combating P. aeruginosa infections. [ABSTRACT FROM AUTHOR]