The evolutionary emergence of multidrug resistant bacterial pathogens

多重耐药细菌病原体的进化出现

• 批准号: BB/R006261/1
• 负责人: Alan McNally
• 金额: $ 52.16万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FR006261%2F1
• 关键词: evolutionary; emergence; multidrug; resistant; bacterial

Increasing antibiotic resistance in bacterial infections is a serious threat to modern medicine, so understanding why some bacteria become resistant to multiple antibiotics whereas others do not is an important challenge for microbiologists, doctors and vets. In pathogenic E. coli - the most common cause of blood and urine infections worldwide and recognised by the World Health Organisation as a top global health threat - antibiotic resistance is associated with gaining extra loops of DNA called plasmids that carry several different antibiotic resistance genes. Not all E. coli strains seem to be able to maintain such plasmids, which is probably because gaining plasmids is typically very costly because the genes the plasmids carry interfere with the workings of the bacterial cell. Our work has led us to hypothesise that this variation between strains of E. coli is due to differences in how the various strains regulate the expression of their genes allowing some to mitigate for the disruption caused to the cell by the plasmid. In this project we will test this idea in the laboratory using evolution experiments and cutting-edge sequencing technology. We have gathered together a collection of plasmid-free E. coli strains whose close relatives do typically carry antibiotic resistance plasmids in nature. First, we will compare the costs of acquiring a plasmid and the level of antibiotic resistance provided in both types of strain. We predict that costs will be higher in strains that don't typically carry plasmids. Second, we will compare the disruption caused to the cell by acquiring a plasmid in both types of strain by measuring patterns of how they express their genes. We predict that disruption to the cell caused by gaining the plasmid will be greater in strains that don't typically carry plasmids, and that this will scale with the costs we measure of carrying the plasmid. Third, we will experimentally evolve bacteria carrying plasmids in the lab to observe in real time how natural selection compensates for the cost of acquiring a plasmid. We predict that evolved bacteria will gain new mutations in regulators that turn genes on or off, to mitigate the disruption to the cell caused by carrying a plasmid, and that this process will be faster and more efficient in strains that typically carry plasmids. Fourth, we will test how the mutations observed during experimental evolution affect the expression of genes in cells with and without plasmids, to understand the molecular mechanisms by which evolution allows bacteria to maintain plasmids. This project will advance our fundamental understanding of how and why pathogenic strains of E. coli that are highly resistant to antibiotics evolve. In future this insight could help us to identify potential superbugs before they emerge, or suggest novel targets for drugs that force bacteria to lose their antibiotic resistance plasmids making them susceptible to conventional treatments.

细菌感染中抗生素耐药性的增加是对现代医学的严重威胁，因此了解为什么有些细菌对多种抗生素产生耐药性，而另一些则没有，这对微生物学家，医生和兽医来说是一个重要的挑战。致病性E.大肠杆菌是全球血液和尿液感染的最常见原因，世界卫生组织认为这是全球最大的健康威胁，抗生素耐药性与获得额外的DNA环（称为质粒）有关，这些质粒携带几种不同的抗生素耐药性基因。不是所有的E。大肠杆菌菌株似乎能够保持这样的质粒，这可能是因为获得质粒通常非常昂贵，因为质粒携带的基因干扰细菌细胞的工作。我们的工作使我们假设，大肠杆菌菌株之间的这种变异。大肠杆菌中的质粒是由于不同菌株如何调节其基因表达的差异，从而允许一些菌株减轻质粒对细胞造成的破坏。在这个项目中，我们将使用进化实验和尖端测序技术在实验室中测试这一想法。我们收集了一批无质粒E。大肠杆菌菌株，其近亲在自然界中通常携带抗生素抗性质粒。首先，我们将比较获得质粒的成本和两种类型菌株的抗生素耐药性水平。我们预测，通常不携带质粒的菌株的成本会更高。其次，我们将通过测量两种类型菌株如何表达其基因的模式，比较通过在两种类型菌株中获得质粒对细胞造成的破坏。我们预测，在通常不携带质粒的菌株中，获得质粒对细胞造成的破坏将更大，并且这将与我们测量的携带质粒的成本成比例。第三，我们将在实验室中实验性地进化携带质粒的细菌，以真实的观察自然选择如何补偿获得质粒的成本。我们预测，进化的细菌将在调节基因的开启或关闭中获得新的突变，以减轻携带质粒对细胞造成的破坏，并且这一过程在通常携带质粒的菌株中将更快，更有效。第四，我们将测试在实验进化过程中观察到的突变如何影响有质粒和无质粒的细胞中基因的表达，以了解进化允许细菌维持质粒的分子机制。该项目将推进我们对致病性大肠杆菌菌株如何以及为什么致病的基本理解。对抗生素有高度抗药性的大肠杆菌进化出来。在未来，这一见解可以帮助我们在潜在的超级细菌出现之前识别它们，或者为药物提供新的靶点，迫使细菌失去抗生素耐药性质粒，使它们对常规治疗敏感。

项目成果

Mapping Gene-by-Gene Single-Nucleotide Variation in 8,535 Mycobacterium tuberculosis Genomes: a Resource To Support Potential Vaccine and Drug Development.

• DOI: 10.1128/msphere.01224-20
• 发表时间: 2021-03-10
• 期刊: mSphere
• 影响因子: 4.8
• 作者: Papakonstantinou D;Dunn SJ;Draper SJ;Cunningham AF;O'Shea MK;McNally A
• 通讯作者: McNally A

Evolutionary Responses to Acquiring a Multidrug Resistance Plasmid Are Dominated by Metabolic Functions across Diverse Escherichia coli Lineages.

• DOI: 10.1128/msystems.00713-22
• 发表时间: 2023-02-23
• 期刊: mSystems
• 影响因子: 6.4

Limited and Strain-Specific Transcriptional and Growth Responses to Acquisition of a Multidrug Resistance Plasmid in Genetically Diverse Escherichia coli Lineages.

• DOI: 10.1128/msystems.00083-21
• 发表时间: 2021-04-27
• 期刊: mSystems
• 影响因子: 6.4
• 作者: Dunn S;Carrilero L;Brockhurst M;McNally A
• 通讯作者: McNally A

Dynamics of intestinal multidrug-resistant bacteria colonisation contracted by visitors to a high-endemic setting: a prospective, daily, real-time sampling study.

• DOI: 10.1016/s2666-5247(20)30224-x
• 发表时间: 2021-04
• 期刊: The Lancet. Microbe
• 作者: Kantele A;Kuenzli E;Dunn SJ;Dance DAB;Newton PN;Davong V;Mero S;Pakkanen SH;Neumayr A;Hatz C;Snaith A;Kallonen T;Corander J;McNally A
• 通讯作者: McNally A

Whole-genome sequencing enhances existing pathogen and antimicrobial-resistance surveillance schemes within a neonatal unit.

• DOI: 10.1099/mgen.0.000841
• 发表时间: 2022-06
• 期刊: MICROBIAL GENOMICS
• 影响因子: 3.9
• 作者: Price, Vivien;Dunn, Steven J.;Moran, Robert A.;Swindells, Jonathan;McNally, Alan
• 通讯作者: McNally, Alan