Plasmid-Bacteria Coevolution Promotes the Spread of Antibiotic Resistance

质粒-细菌共同进化促进抗生素耐药性的传播

基本信息

批准号：
10395990
负责人：
Eva M. Top
金额：
$ 36.67万
依托单位：
UNIVERSITY OF IDAHO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10395990
关键词：
Abate Affect Antibiotic Resistance Antibiotics Bacteria Biochemical Biological Assay Cause of Death Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Computer Simulation Data Development Drug resistance Evolution Experimental Designs Genes Goals Health Helicase Gene Horizontal Gene Transfer Human Joints Lead Link Mediating Mobile Genetic Elements Molecular Multi-Drug Resistance Multiple Bacterial Drug Resistance Mutation Pharmaceutical Preparations Plasmids Prevalence Process Proteins Pseudomonas aeruginosa Resistance Resort Role Statistical Models Techniques Testing Time Work World Health World Health Organization cost experimental study fitness health organization helicase improved insight mathematical model models and simulation multi-drug resistant pathogen multidisciplinary new therapeutic target novel novel therapeutics pathogen pathogenic bacteria permissiveness repository resistance gene trait

项目摘要

PROJECT SUMMARY/ABSTRACT Many leading human health organizations such as the World Health Organization and the Centers for Disease Control and Prevention (CDC) have declared that the increased prevalence of bacterial pathogens that are resistant to multiple antibiotics is a significant human health crisis. The emergence of these multi-drug resistant (MDR) pathogens is largely due to the sharing of resistance genes by plasmid mediated horizontal gene transfer. Bacterial plasmids are mobile genetic elements that can confer resistance to a variety of antibiotics, including those that are considered to be “drugs of last resort”. Our long-term goal is to aid the development of strategies that can slow the spread of antibiotic resistance by gaining insight into the co-evolutionary processes that allow bacteria to improve the persistence of newly acquired MDR plasmids. Newly acquired resistance plasmids often do not persist in the absence of antibiotics, but we and others have shown that single mutations in the bacterial host, the plasmid, or both can rapidly improve this persistence. We and others also identified critical mutations in chromosomally encoded accessory helicases. Plasmid-helicase interactions in bacteria may therefore be key to the ability of bacterial pathogens to retain newly acquired MDR plasmids. Unfortunately, the molecular mechanisms that explain the positive effects of these mutations on plasmid persistence are unknown. Importantly, we also showed for the first time that these mutations pre-adapt the bacteria to other MDR plasmids that they acquire later in time, leading to their enhanced persistence (referred to as increased plasmid permissiveness). This suggests that bacteria with increased permissiveness can serve as stable repositories for multiple MDR plasmids, eventually generating strains with an expanded arsenal of resistance genes. This possibility has never been tested. Using molecular techniques, experimental evolution and mathematical modeling, we propose to test the following hypotheses: (i) chromosomal mutations can pre- adapt bacteria to other plasmids, leading to greater plasmid permissiveness; (ii) plasmid permissiveness can expand the spectrum of antibiotic resistance traits within a bacterial species; and (iii) accessory helicases are linked to the persistence of newly acquired MDR plasmids across a wide spectrum of bacterial pathogens. This will be done through achieving the following Specific Aims: (1) Test the generality of (i) increased plasmid permissiveness after host/plasmid coevolution, and (ii) helicase mutations as a mechanism of host adaptation to novel MDR plasmids.; (2) determine the effects of plasmid persistence and permissiveness on the emergence of expanded drug resistance; (3) determine the molecular mechanism of plasmid cost amelioration resulting from mutations in accessory helicases. If our hypotheses are supported by our data, mutations that stabilize one plasmid could lead to improved persistence of other plasmids, and expand the arsenal of resistance genes in the same cell. Our findings will aid the development of new therapies aimed at slowing down the spread of antibiotic resistance in bacterial pathogens.!

项目概要/摘要许多领先的人类健康组织，例如世界卫生组织和疾病中心控制与预防 (CDC) 宣布，细菌性病原体的流行率增加对多种抗生素产生耐药性是人类健康的重大危机，这些多重耐药性的出现。（MDR）病原体很大程度上是由于质粒介导的水平基因共享抗性基因细菌质粒是可移动的遗传元件，可以赋予对多种抗生素的抗性，包括那些被认为是“最后手段”的药物，我们的长期目标是帮助发展。通过深入了解共同进化来减缓抗生素耐药性传播的策略使细菌能够提高新获得的 MDR 质粒的持久性的过程。抗性质粒在没有抗生素的情况下通常不会持续存在，但我们和其他人已经证明细菌宿主、质粒或两者的单一突变可以迅速提高这种持久性。还鉴定了染色体编码的辅助解旋酶相互作用的关键突变。因此，细菌中的 MDR 可能是细菌病原体保留新获得的 MDR 质粒的能力的关键。不幸的是，解释这些突变对质粒的积极影响的分子机制重要的是，我们还首次表明这些突变预先适应了。细菌与它们稍后获得的其他 MDR 质粒结合，导致它们的持久性增强（称为增加的质粒许可性）这表明具有增加的许可性的细菌可以发挥作用。作为多个 MDR 质粒的稳定储存库，最终产生具有扩展库的菌株抗性基因从未使用分子技术、实验进化进行过测试。和数学模型，我们建议测试以下假设：（i）染色体突变可以预先 (ii) 质粒许可性可以使细菌适应其他质粒，从而导致更大的质粒许可性；扩大细菌物种内的抗生素抗性特征谱；以及 (iii) 辅助解旋酶与新获得的 MDR 质粒在多种细菌病原体中的持久性有关。将通过实现以下具体目标来完成： (1) 测试 (i) 增加质粒的普遍性宿主/质粒共同进化后的许可性，以及（ii）解旋酶突变作为宿主的机制适应新的 MDR 质粒。（2）确定质粒持久性的影响和 (3)确定耐药性扩大出现的分子许可程度；如果我们的辅助解旋酶突变导致质粒成本改善的机制。我们的数据支持假设，稳定一个质粒的突变可能会导致持久性的提高其他质粒，并扩大同一细胞中的抗性基因库，我们的发现将有助于开发旨在减缓细菌病原体抗生素耐药性传播的新疗法。！

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Strain-specific transfer of antibiotic resistance from an environmental plasmid to foodborne pathogens.

DOI：
10.1155/2012/834598
发表时间：
2012
期刊：
Journal of biomedicine & biotechnology
影响因子：
0
作者：
Van Meervenne E;Van Coillie E;Kerckhof FM;Devlieghere F;Herman L;De Gelder LS;Top EM;Boon N
通讯作者：
Boon N

Estimating the transfer rates of bacterial plasmids with an adapted Luria-Delbrück fluctuation analysis.

DOI：
10.1371/journal.pbio.3001732
发表时间：
2022-07
期刊：
PLOS BIOLOGY
影响因子：
9.8
作者：
Kosterlitz, Olivia;Tirado, Adamaris Muniz;Wate, Claire;Elg, Clint;Bozic, Ivana;Top, Eva M.;Kerr, Benjamin
通讯作者：
Kerr, Benjamin

Plasmid transfer in biofilms: a perspective on limitations and opportunities.