两种类型的DNA基拉酶抑制剂引起了不同的进化轨迹,导致格兰负病原体的耐药性
Semen A Leyn1, James E Kent1, Jaime E Zlamal1
1Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
bioRxiv : the preprint server for biology
|July 10, 2023
概括
了解抗菌素耐药性是开发新药的关键. 这项研究表明,大肠杆菌和A. baumannii对DNA回旋酶抑制剂GP6的耐药性主要涉及排泄的上调,与西普洛素耐药性不同.
科学领域:
- 微生物学 微生物学
- 分子生物学分子生物学
- 药物发现 药物发现 药物发现
背景情况:
- 抗菌素耐药性 (AMR) 构成了全球健康的重大威胁.
- 开发新的抗生素需要深入了解耐药机制.
- DNA 陀螺酶和陀螺酶抑制剂是关键的抗生素类别.
研究的目的:
- 在大肠杆菌和Acinetobacter baumannii*中研究抗DNA旋酶/拓酶TriBE抑制剂GP6的进化动态.
- 为了比较GP6的耐药性机制与西普洛素 (CIP) 的耐药性机制.
主要方法:
- 在一个病态定位器,一个连续培养装置中利用实验进化.
- 采用了进化文化的全基因组测序.
- 鉴定耐药分离物的特征,以确定耐药机制.
主要成果:
- 通过目标突变 (GyrB子单元) 和排水上调 (例如,AcrAB/TolC,AdeIJK,MdtK) 进化了GP6耐药性.
- 溢出升调是GP6的主导阻力机制,有时会先于目标修改.
- 抗GP6的分离体对西普洛素呈现交叉耐药性,但不是反之亦然.
结论:
- 对GP6和西普洛素的耐药性涉及不同的进化途径和向突变.
- 排泄活动在GP6耐药性中起着关键作用,使其与其他药物交叉耐药.
- 了解这些不同的机制对于设计下一代抗生素具有降低耐药性潜力的设计至关重要.
相关概念视频
Development of Antibiotic Resistance
42
Antibiotic resistance is a major public health concern that arises when bacteria evolve mechanisms to withstand the effects of antibiotic treatments. This resistance can be intrinsic, acquired through genetic mutations, or transferred between bacteria via horizontal gene transfer. The development of antibiotic resistance poses significant challenges in treating bacterial infections and necessitates ongoing research to develop new therapeutic strategies.Intrinsic resistance occurs when bacterial...
42
Genomic DNA in Prokaryotes
44.1K
The genome of most prokaryotic organisms consists of double-stranded DNA organized into one circular chromosome in a region of cytoplasm called the nucleoid. The chromosome is tightly wound, or supercoiled, for efficient storage. Prokaryotes also contain other circular pieces of DNA called plasmids. These plasmids are smaller than the chromosome and often carry genes that confer adaptive functions, such as antibiotic resistance.
Genomic Diversity in Bacteria
Although bacterial genomes are much...
Genomic Diversity in Bacteria
Although bacterial genomes are much...
44.1K
Antibiotic Selection
54.8K
Overview
54.8K
Gene Regulation in Microbial Communities: Quorum Sensing
41
Quorum sensing is a mechanism of bacterial communication that enables coordinated gene expression in response to changes in population density. This facilitates collective behaviors that enhance survival, resource acquisition, and ecological adaptation. This process relies on small signaling molecules called autoinducers that accumulate as bacterial populations grow. When a critical threshold concentration of autoinducers is reached, bacterial cells collectively modify gene expression,...
41
Gene Evolution - Fast or Slow?
7.2K
The genomes of eukaryotes are punctuated by long stretches of sequence which do not code for proteins or RNAs. Although some of these regions do contain crucial regulatory sequences, the vast majority of this DNA serves no known function. Typically, these regions of the genome are the ones in which the fastest change, in evolutionary terms, is observed, because there is typically little to no selection pressure acting on these regions to preserve their sequences.
In contrast, regions which code...
In contrast, regions which code...
7.2K
Stringent Response in E. coli
31
Bacterial growth is closely tied to nutrient availability, with cells proliferating exponentially under favorable conditions and entering a stationary phase when resources become scarce. This transition is mediated by a regulatory mechanism known as the stringent response, which allows bacteria to adapt to nutrient deprivation by modulating gene expression and metabolic activity.During nutrient scarcity, intracellular amino acid levels decline. It results in the accumulation of uncharged tRNAs...
31


