期刊
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
卷 66, 期 7, 页码 -出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/aac.00421-22
关键词
Pseudomonas aeruginosa; aztreonam/avibactam; beta-lactam antibiotics; PA4292; antibiotic resistance; pyocyanin
资金
- National Key Research and Development Project of China [2021YFE0101700, 82061148018]
- National Science Foundation of China [32170177, 32170199, 31970680, 31970179, 31870130]
- Fundamental Research Funds for the Central Universities [63213121]
Aztreonam/avibactam is an effective drug against Metallo-beta-lactamase (MBL)-producing Pseudomonas aeruginosa, a pathogen causing highly lethal infections. This study discovered a novel gene mutation, PM292, that could lead to resistance to aztreonam/avibactam and beta-lactams. Additionally, the study found that overproduction of pyocyanin increased bacterial resistance to beta-lactams.
Metallo-beta-lactamase (MBL)-producing Pseudomonas aeruginosa is increasingly reported worldwide and usually causes infections with high mortality rates. Aztreonam/avibactam is a beta-lactam/beta-lactamase inhibitor (BLBLI) combination that is under clinical trials. The advantage of aztreonam/avibactam over the currently used BLBLIs lies in its effectiveness against MBL-producing pathogens, making it one of the few drugs that can be used to treat infections caused by MBL-producing P. aeruginosa. However, the molecular mechanisms underlying aztreonam/avibactam resistance development remain unexplored. Here, in this study, we performed an in vitro evolution assay by using a previously identified MBL-producing P. aeruginosa clinical isolate, NKPa-71, and found mutations in a novel gene, PM292, in the aztreonam/avibactam-resistant mutants. By mutation of PA4292 in the reference strain PA14, we verified the role of PA4292 in the resistance to aztreonam/avibactam and beta-lactams. Transcriptomic analyses revealed upregulation of pyocyanin biosynthesis genes among the most overexpressed in the PA4292 mutant. We further demonstrated that pyocyanin overproduction in the PA4292 mutant increased the bacterial resistance to beta-lactams by reducing drug influx. These data revealed a novel mechanism that might lead to the development of resistance to aztreonam/avibactam and beta-lactams.
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