Huan Ren1, Yiwei Liu1, Jingyi Zhou1, Yuqing Long1, Chang Liu1, Bin Xia1, Jing Shi1, Zheng Fan1, Yuying Liang2, Shuiping Chen2, Jun Xu3, Penghua Wang3, Yanhong Zhang4, Guangbo Zhu5, Huimin Liu5, Yongxin Jin1, Fang Bai1, Zhihui Cheng1, Shouguang Jin6, Weihui Wu1. 1. State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Molecular Microbiology and Technology of the Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin, China. 2. Department of Infection and Control, 307 hospital, Beijing, China. 3. NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, and Diabetic foot Department, Tianjin Medical University Metabolic Disease Hospital and Chu Hsien-I Memorial Hospital, Tianjin, China. 4. Nankai University Affiliated Hospital (Tianjin Forth Hospital), Tianjin, China. 5. Tianjin Union Medical Center, Nankai University Affiliated Hospital, Tianjin, China. 6. Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville.
Abstract
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.
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.
Authors: Stijn P Andeweg; Rutger M Schepp; Jan van de Kassteele; Liesbeth Mollema; Guy A M Berbers; Michiel van Boven Journal: Sci Rep Date: 2021-04-26 Impact factor: 4.379
Authors: Rakel Arrazuria; Bernhard Kerscher; Karen E Huber; Jennifer L Hoover; Carina Vingsbo Lundberg; Jon Ulf Hansen; Sylvie Sordello; Stephane Renard; Vincent Aranzana-Climent; Diarmaid Hughes; Philip Gribbon; Lena E Friberg; Isabelle Bekeredjian-Ding Journal: Front Microbiol Date: 2022-09-08 Impact factor: 6.064