Molecular basis of outer membrane stabilisation by the energised Tol-Pal system in Gram-negative bacteria

革兰氏阴性菌通电 Tol-Pal 系统外膜稳定的分子基础

基本信息

  • 批准号:
    BB/V008056/1
  • 负责人:
  • 金额:
    $ 127.86万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2021
  • 资助国家:
    英国
  • 起止时间:
    2021 至 无数据
  • 项目状态:
    未结题

项目摘要

Bacteria are important for the health and well-being of most living organisms on earth. Examples in humans include their importance in our gut microbiomes for the digestion of food. Bacteria can also be pathogenic, meaning they can infect tissues and organs which, if left untreated, can be lethal. Much of modern medicine relies on the effective treatment of bacterial infections, such as pneumonia and sepsis, through the use of antibiotics. The rise of antibiotic resistance in bacteria is increasingly rendering many of our frontline antibiotics ineffective.The current proposal focuses on the outer membrane, one of the main factors contributing to antibiotic resistance in Gram-negative bacteria such as Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae. The outer membrane is a highly impermeable barrier that excludes many types of antibiotics that are otherwise effective against Gram-positive bacteria that lack an outer membrane. During the process of division in Gram-negative bacteria newly replicated daughter cells must have their individual outer membranes pinned to the underlying cell wall. This process requires the input of energy. Because the outer membrane is an 'energy-less' environment the requisite energy is provided by the electrochemical gradient across the inner membrane of the bacterium. A complex, multiprotein protein nanomachine known as Tol-Pal is tasked with this transfer of energy. Tol-Pal taps into this energy source to stabilise the outer membrane by an unknown mechanism.We discovered recently how Tol-Pal achieves this complex function, in the process identifying a biological mechanism we call 'mobilisation-and-capture'. The current proposal seeks to capitalise on these advances. We will investigate all the discrete interactions of the five Tol-Pal components and how they move in the membranes of the bacterium in order to understand how the cell's energy is exploited to pin the outer membrane to the cell wall. As part of this work, we will also exploit a new technology we have developed whereby energised complexes in Gram-negative bacteria can be trapped in their activated states for subsequent structural dissection using antibacterial proteins known as colicins.Through this work we will obtain the most detailed view yet of how the outer membrane is stabilised in Gram-negative bacteria and how nanomachines like Tol-Pal work to achieve this, knowledge that can be exploited in the future fight against bacterial infections.
细菌对地球上大多数生物的健康和福祉都很重要。人类的例子包括它们在我们消化食物的肠道微生物组中的重要性。细菌也可以是致病性的,这意味着它们可以感染组织和器官,如果不加以治疗,可能是致命的。许多现代医学依赖于通过使用抗生素有效治疗细菌感染,如肺炎和败血症。细菌对抗生素耐药性的上升正日益使我们的许多一线抗生素失效。目前的建议集中在外膜上,这是导致革兰氏阴性菌(如大肠杆菌、铜绿假单胞菌和肺炎克雷伯菌)耐药性的主要因素之一。外膜是一个高度不可渗透的屏障,排除了许多类型的抗生素,这些抗生素对缺乏外膜的革兰氏阳性菌有效。在革兰氏阴性菌的分裂过程中,新复制的子细胞必须有其单独的外膜固定在下面的细胞壁上。这个过程需要能量的输入。因为外膜是一个“无能量”的环境,所以所需的能量由细菌内膜上的电化学梯度提供。一个复杂的,多蛋白质的蛋白质纳米机器被称为Tol-Bronze的任务是这种能量的转移。我们最近发现了Tol-doppler是如何实现这一复杂功能的,在这个过程中,我们发现了一种我们称之为“动员和捕获”的生物机制。目前的提案旨在利用这些进步。我们将研究五种Tol-binding组分的所有离散相互作用以及它们如何在细菌的膜中移动,以了解细胞的能量如何被利用来将外膜固定在细胞壁上。作为这项工作的一部分,我们还将利用我们开发的一种新技术,通过这种技术,革兰氏阴性细菌中的能量复合物可以被捕获在其激活状态下,用于随后的结构解剖,使用被称为大肠杆菌素的抗菌蛋白。通过这项工作,我们将获得最详细的视图,了解革兰氏阴性细菌的外膜是如何稳定的,以及纳米机器如Tol-Bronx如何实现这一目标,这些知识可以在未来对抗细菌感染的斗争中加以利用。

项目成果

期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Tunable force transduction through the Escherichia coli cell envelope.
Lipids mediate supramolecular outer membrane protein assembly in bacteria.
  • DOI:
    10.1126/sciadv.adc9566
  • 发表时间:
    2022-11-04
  • 期刊:
  • 影响因子:
    13.6
  • 作者:
  • 通讯作者:
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Colin Kleanthous其他文献

Nanoscale Protein Interactions Determine the Mesoscale Dynamic Organisation of Biomembranes
  • DOI:
    10.1016/j.bpj.2017.11.2163
  • 发表时间:
    2018-02-02
  • 期刊:
  • 影响因子:
  • 作者:
    Anna L. Duncan;Matthieu Chavent;Patrice Rassam;Jean Hélie;Tyler Reddy;Oliver Birkholz;Dmitry Belyaev;Ben Hambly;Jacob Piehler;Colin Kleanthous;Mark S.P. Sansom
  • 通讯作者:
    Mark S.P. Sansom
Force Triggered Dissociation of the Highly Avid E9:Im9 Complex
  • DOI:
    10.1016/j.bpj.2012.11.3174
  • 发表时间:
    2013-01-29
  • 期刊:
  • 影响因子:
  • 作者:
    David Brockwell;Oliver Farrance;Renata Kaminska;Sasha Derrington;Colin Kleanthous;Sheena Radford
  • 通讯作者:
    Sheena Radford
MPSA abstracts
  • DOI:
    10.1007/bf01898856
  • 发表时间:
    1994-07-01
  • 期刊:
  • 影响因子:
    1.400
  • 作者:
    Mahmoud Aminlari;Thomas Asquith;Katherine Sarlo;Jerome M. Bailey;Oanh Tu;Gilbert Issai;Alice Ha;John E. Shively;Alexander W. Bell;Nicole C. Baur;John J. M. Bergeron;Wei -Jia Ou;David Y. Thomas;Katherine Cianflone;Allain Baldo;Maxwell T. Hincke;Richard L. Momparler;Josée Laliberté;David M. P. Thomson;M. Sutherland;Vladimir Besada;Javier Gonzalez;Gabriel Padron;Hilda Garay;Osvaldo Reyes;Toshifumi Takao;Yasutsugu Shimonishi;Rainer Bischoff;Dominique Roecklin;Bernadette Bouchon;Klaus Klarskov;Alain Van Dorsselaer;Patricia G. Brake;Anne Pacitti;Terry Higgins;Panos Stevis;John Malinowski;Sue McElhiney;Janes Huang;Christine Vestal;Scott D. Buckel;Tracy Stevenson;Joseph A. Loo;Martin Caffrey;Jin Wang;Carmichael J. A. Wallace;Ian Clark-Lewis;C. A. Carothers Carraway;J. Huang;Y. Li;S. -H. Juang;A. Gallo;B. J. Mayer;K. L. Carraway;Patrick L. Coleman;Daniel Sarpong;David W. Deerfield;Amanda Holland-Minkley;John D. Hempel;Hugh B. Nicholas;Nancy D. Denslow;Leroy C. Folmar;Craig V. Sullivan;James D. Dixon;Jonathan P. Mark;Christopher P. Elicone;Simin D. Maleknia;Brian F. McGuinness;Fred E. Regnier;Noubar B. Afeyan;Julia M. Dolence;C. Dale Poulter;Tsezi Egorov;Alexander Musolyamov;Yves Popineau;Jens Andersen;Peter Roepstorff;Roberto J. Falkenstein;Mirtha J. Biscoglio de Jiménez Bonino;Clara Peña;D. L. Gauggel;T. N. Asquith;R. J. Isfort;N. S. Miller;D. B. Cody;Michael F. Giblin;Tuck C. Wong;Thomas P. Quinn;Gregory A. Grant;Mark W. Crankshaw;Scott Griffith;Steve Schroeder;Thomas Quinn;F. Guinet;Y. Petillot;J. M. Chapsal;J. Dubayle;F. Greco;O. Barge;E. Forest;C. Valentin;Frederick M Hahn;Jonathan A. Baker;C. Dale Poulter;Mitsuru Haniu;William C. Kenney;Michael F. Rohde;James G. Harman;Eun Ju Lee;Joel Glasgow;Sew Fen Lew;Ali O. Belduz;Reed J. Harris;Michael S. Molony;Lene H. Keyt;Shiaw -Lin Wu;David H. Hawke;Jaqueline Tso;Sherrell Early;Chad G. Miller;G. Thomas Hayman;Jan A. Miernyk;Ulf Hellman;Christer Wernstedt;Jorge Góñez;Daniel Hess;Ralph Studer;Peter E. Hunziker;Hisashi Hirano;Yoshihiro Watanabe;Sergei F. Barbashov;Setsuko Komatsu;Andrew M. Hemmings;Masaru Miyagi;Susumu Tsunasawa;Reuben E. Huber;Nathan J. Roth;Michael T. Gaunt;Paul Jenö;Thierry Mini;Suzette Moes;Martin Horst;Kenji Jinnai;Tetsuo Ashizawa;M. Zouhair Atassi;Anders H. Johnsen;Hanne Jensen;Jens F. Rehfeld;Masaharu Kamo;Takao Kawakami;Norifumi Miyatake;Akira Tsugita;JN Keen;PF Zagalsky;JBC Findlay;Regine Kraft;Susanne Kostka;Enno Hartmann;Henry C. Krutzsch;John K. Inman;Claudia Machalinski;Mirtha Biscoglio de Jiménez Bonino;Donald K. McRorie;Gregg R. Dieckmann;Susan Heilman;William F. DeGrado;Vincent L. Pecoraro;James Kenny;Julie Sahakian;Jacqueline Tso;Mary B. Moyer;William A. Burkhart;Tatyana Muranova;Lubov Makova;Hugh Nicholas;John Hempel;Amy Hinich;David Deerfield;Joseph Behrmann;Alex Ropelewski;Lori Nixon;Leonard Maneri;Kerry Nugent;Ken Stoney;John Wieser;Hiroshi Ohguro;Krzysztof Palczewski;Kenneth A. Walsh;Richard S. Johnson;Leonard C Packman;Carl Webster;John Gray;G. Padrón;V. Morera;L. J. González;Y. Támbara;V. Besada;R. Villalonga;G. Chinea;O. Reyes;H. Garay R. Bringas;C. Nazábal;Bruce P. Parkinson;Kent A. Yamada;Anne Randolph;Anthony Pisano;Nicole H. Packer;John W. Redmond;Keith L. Williams;Andrew A. Gooley;Hanne H. Rasmussen;Ejvind Mørtz;Matthias Mann;Julio E. Celis;Lone K. Rasmussen;Esben S. Sørensen;Torben E. Petersen;Jørgen Gliemann;Poul Henning Jensen;Staffan Renlund;Henrik Wadensten;Annika Persson;Per Persson;Agneta Johansson;Per -Olof Edlund;Donald J. Rose;Ragna Sack;Alex Apffel;Chad Miller;Rodney L. Levine;Kazuyasu Sakaguchi;Nicola Zambrano;Marc S. Lewis;Eric T. Baldwin;Bruce A. Shapiro;John W Erickson;James G. Omichinski;G. Marius Clore;Angela M. Gronenborn;Ettore Appella;Werner Schröder;Irmgard Moser;Werner Pansegrau;Erich Lanka;Richard J. Simpson;James Eddes;Hong Ji;Gavin E. Reid;Robert L. Moritz;Peter Højrup;David W. Speicher;David F. Reim;Kaye D. Speicher;B. R. Srinivasa;S. P. Barde;William G. Stirtan;Alyona Sukhanova;Sergey Vorob'ev;Alexander Gabibov;Igor Bronstein;Kenji Tanaka;Kuniko Einaga;Minoru Tsukada;Jonathan F. Tait;Kazuo Fujikawa;Keiji Takamoto;Kazuo Satake;Ilya A. Vakser;V. V. Velikodvorskaia;A. G. Gabibov;A. G. Rabinkov;Tennie Videler;Michael Osborne;Geoffrey Moore;Richard James;Colin Kleanthous;Jane H. Walent;Richard Bessen;Dick Marsh;G. Marius Clore;Ronald L. Niece;Francis H. C. Tsao;Hong Wang;Scot R. Weinberger;Lynn M. Chakel;Ewald M. Wondrak;Alan R. Kimmel;John M. Louis
  • 通讯作者:
    John M. Louis
How Nanoscale Protein Interactions Determine the Mesoscale Dynamic Organisation of Membrane Proteins
  • DOI:
    10.1016/j.bpj.2018.11.1984
  • 发表时间:
    2019-02-15
  • 期刊:
  • 影响因子:
  • 作者:
    Anna L. Duncan;Maximilian A.R. Bandurka;Matthieu G. Chavent;Patrice Rassam;Wanling Song;Oliver Birkholz;Jean Helie;Tyler Reddy;Dmitry Beliaev;Ben Hambly;Jacob Piehler;Colin Kleanthous;Mark S.P. Sansom
  • 通讯作者:
    Mark S.P. Sansom
Letter to the Editor: Assignment of 1H,13C and 15N signals of the DNase domain of colicin E9
  • DOI:
    10.1023/a:1008394407597
  • 发表时间:
    1999-06-01
  • 期刊:
  • 影响因子:
    1.900
  • 作者:
    Sara B.-M. Whittaker;Ruth Boetzel;Colin MacDonald;Lu-Yun Lian;Richard James;Colin Kleanthous;Geoffrey R. Moore
  • 通讯作者:
    Geoffrey R. Moore

Colin Kleanthous的其他文献

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{{ truncateString('Colin Kleanthous', 18)}}的其他基金

Pushing the envelope: atomic force microscopy imaging of the bacterial outer membrane during growth and division
挑战极限:生长和分裂过程中细菌外膜的原子力显微镜成像
  • 批准号:
    BB/X007669/1
  • 财政年份:
    2024
  • 资助金额:
    $ 127.86万
  • 项目类别:
    Research Grant
Exploiting protein import to interrogate energy transduction through the bacterial cell envelope
利用蛋白质输入来询问通过细菌细胞包膜的能量转导
  • 批准号:
    BB/X016366/1
  • 财政年份:
    2024
  • 资助金额:
    $ 127.86万
  • 项目类别:
    Research Grant
Protein import through the E. coli cell envelope
通过大肠杆菌细胞膜输入蛋白质
  • 批准号:
    BB/P009948/1
  • 财政年份:
    2017
  • 资助金额:
    $ 127.86万
  • 项目类别:
    Research Grant
Molecular basis of protein translocation through outer membrane porins
蛋白质通过外膜孔蛋白易位的分子基础
  • 批准号:
    BB/L021234/1
  • 财政年份:
    2015
  • 资助金额:
    $ 127.86万
  • 项目类别:
    Research Grant
Molecular mechanism of environmental stress sensing by bacterial Zinc-containing Anti-Sigma factors
细菌含锌Anti-Sigma因子感知环境应激的分子机制
  • 批准号:
    BB/I008691/2
  • 财政年份:
    2012
  • 资助金额:
    $ 127.86万
  • 项目类别:
    Research Grant
Investigating E. coli cell envelope proteins and processes through colicin intoxication
通过大肠菌素中毒研究大肠杆菌细胞包膜蛋白和过程
  • 批准号:
    BB/G020671/2
  • 财政年份:
    2012
  • 资助金额:
    $ 127.86万
  • 项目类别:
    Research Grant
Molecular mechanism of environmental stress sensing by bacterial Zinc-containing Anti-Sigma factors
细菌含锌Anti-Sigma因子感知环境应激的分子机制
  • 批准号:
    BB/I008691/1
  • 财政年份:
    2011
  • 资助金额:
    $ 127.86万
  • 项目类别:
    Research Grant
Investigating E. coli cell envelope proteins and processes through colicin intoxication
通过大肠菌素中毒研究大肠杆菌细胞包膜蛋白和过程
  • 批准号:
    BB/G020671/1
  • 财政年份:
    2009
  • 资助金额:
    $ 127.86万
  • 项目类别:
    Research Grant
Biophysical and structural analysis of protein-protein interactions: from encounter complexes to computational design and directed evolution
蛋白质-蛋白质相互作用的生物物理和结构分析:从相遇复合物到计算设计和定向进化
  • 批准号:
    BB/E011306/1
  • 财政年份:
    2007
  • 资助金额:
    $ 127.86万
  • 项目类别:
    Research Grant

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Molecular basis of mammalian cochlear regeneration
哺乳动物耳蜗再生的分子基础
  • 批准号:
    10682272
  • 财政年份:
    2023
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外视网膜发育和修复的分子基础的多样性补充剂(Pilar Andrade)
  • 批准号:
    10428900
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Molecular Basis of Outer Retina Development and Repair
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Molecular Basis of Rod and Cone Photoreceptor Outer Segment Structures
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Molecular Basis for Substrate Recognition of Outer Membrane Proteins of the Human Pathogen Pseudomonas Aeruginosa
人类病原体铜绿假单胞菌外膜蛋白底物识别的分子基础
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    BB/M029573/1
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    2016
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