期刊
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
卷 12, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fcimb.2022.920761
关键词
Klebsiella pneumoniae; tigecycline; aminoglycoside; combination therapy; hypersensitivity
资金
- National Natural Science Foundation of China [81903672]
- China International Medical Foundation [Z-2018-35-2003]
- Peking University People's Hospital Research and Development Funds [RS2020-04]
This study used proteomics analysis to investigate the impact and mechanism of tigecycline and aminoglycoside combination therapy on carbapenem-resistant Klebsiella pneumoniae (CRKP). The study found that the proteomic responses to tigecycline and aminoglycosides were different in monotherapy, with tigecycline dominating the proteomic alterations in combination therapy. Adaptive responses to tigecycline were associated with the upregulation of oxidative phosphorylation and translation-related proteins, while tigecycline might perturb adaptive responses to aminoglycosides through inhibition of heat shock response.
Co-administration of antibiotics with synergistic effects is one method to combat carbapenem-resistant organisms. Although the synergistic effects of tigecycline combined with aminoglycosides against carbapenem-resistant Klebsiella pneumoniae (CRKP) have been demonstrated in vitro and in animal models, the underlying mechanism remains elusive. Here we used proteomics analysis to assess the short-term bacterial responses to tigecycline and aminoglycosides alone or in combination. Emergence of tigecycline resistance during treatment and the susceptibility of tigecycline-resistant strains to aminoglycosides was further evaluated. The proteomic responses to tigecycline and aminoglycosides were divergent in monotherapy, with proteomic alterations to combination therapy dominated by tigecycline. Adaptive responses to tigecycline were associated with the upregulation of oxidative phosphorylation and translation-related proteins. These responses might confer CRKP hypersensitivity towards aminoglycosides by increasing the drug uptake and binding targets. Meanwhile, tigecycline might perturb adaptive responses to aminoglycosides through inhibition of heat shock response. Tigecycline-resistant strains could be isolated within 24 h exposure even in strains without heteroresistance, and the sensitivity to aminoglycosides significantly increased in resistant strains. Overall, these findings demonstrated that adaption to tigecycline in CRKP was a double-edged sword associated with the synergistic killing in tigecycline-aminoglycoside combination. Evolutionary hypersensitivity can provide novel insight into the mechanisms of antibiotic synergistic effects.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据