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BactoDrug

The Bacteroides dual-pumping membrane-integral pyrophosphatase: a novel drug target

Total Cost €

0

EC-Contrib. €

0

Partnership

0

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 BactoDrug project word cloud

Explore the words cloud of the BactoDrug project. It provides you a very rough idea of what is the project "BactoDrug" about.

convert    questions    bacteria    thermotoga    small    career    channel    outstanding    pyrophosphatases    escape    drug    resonance    couple    single    mechanics    vulgatus    pathogenesis    technologies    membrane    infections    species    pyrophosphatase    play    radiata    collapse    crystallography    opened    explore    kinetics    relation    despite    possess    ion    molecular    molecules    perspectives    though    gut    formed    generate    rate    ions    structure    solved    bacteremia    dual    resistance    charged    mutational    internal    19    pumping    total    anaerobic    human    trap    integral    ppase    structures    closed    cleavage    pore    modeling    flora    conformational    vigna    maritima    abscess    microscopy    conformation    movement    healthy    mortality    stressors    antibiotic    plugged    rates    guide    simulate    fluorescence    energy    date    function    select    utilizing    pursuing    reflection    bacteroides    candidates    na    bacterial    form    transfer    ray    gate    regarding    residues    molecule    ppases   

Project "BactoDrug" data sheet

The following table provides information about the project.

Coordinator
UNIVERSITY OF LEEDS 

Organization address
address: WOODHOUSE LANE
city: LEEDS
postcode: LS2 9JT
website: www.leeds.ac.uk

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country United Kingdom [UK]
 Project website http://www.astbury.leeds.ac.uk/people/staff/staffpage.php
 Total cost 183˙454 €
 EC max contribution 183˙454 € (100%)
 Programme 1. H2020-EU.1.3.2. (Nurturing excellence by means of cross-border and cross-sector mobility)
 Code Call H2020-MSCA-IF-2014
 Funding Scheme MSCA-IF-EF-ST
 Starting year 2015
 Duration (year-month-day) from 2015-06-01   to  2017-05-31

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    UNIVERSITY OF LEEDS UK (LEEDS) coordinator 183˙454.00

Map

 Project objective

Membrane-integral pyrophosphatases (M-PPases) couple cleavage of pyrophosphatase to pumping of ions across a membrane to generate membrane potential and play an important role in resistance to stressors. The solved structures of an H-pumping M-PPase from Vigna radiata and an Na-pumping M-PPase from Thermotoga maritima show M-PPases form a channel through the membrane, and this channel is plugged by an ion gate formed by three charged residues. Despite these structures, there are still many outstanding questions regarding M-PPases, especially in relation to H and Na dual-pumping M-PPases.

Bacteroides species are a major cause of anaerobic infections, and though they are part of a healthy human gut flora, when these bacteria escape the gut, they can cause bacteremia and abscess formation. Bacteroides species are associated with high antibiotic resistance rates and have a 19% or greater mortality rate. However, they do possess a possible drug target: an H/Na-pumping M-PPase.

A major goal of this project is to solve the structure of the Bacteroides vulgatus H/Na-pumping M-PPase to guide mutational studies to determine how M-PPases select for ions and to explore how the ion gate is opened and closed during ion pumping. Since the ion gate is closed in all M-PPase structures to date, I will also use single molecule fluorescence resonance energy transfer and total internal reflection fluorescence microscopy to determine the kinetics and conformational changes during ion gate movement. Finally, I will use molecular mechanics modeling to simulate ion gate function and design small-molecule drug candidates. Molecules that trap the ion gate in the open conformation will convert M-PPase into a pore in the membrane of Bacteroides species, leading to collapse of the membrane potential.

This project will further my career goal of pursuing research in bacterial pathogenesis from various perspectives, utilizing X-ray crystallography and single molecule technologies.

 Publications

year authors and title journal last update
List of publications.
2017 Shah NR, Wilkinson C, Harborne SP, Turku A, Li KM, Sun YJ, Harris S, Goldman A.
Insights into the mechanism of membrane pyrophosphatases by combining experiment and computer simulation.
published pages: , ISSN: 2329-7778, DOI:
Structural Dynamics 2019-07-24
2016 Nita R. Shah, Keni Vidilaseris, Henri Xhaard, Adrian Goldman
Integral membrane pyrophosphatases: a novel drug target for human pathogens?
published pages: 171-194, ISSN: 2377-9098, DOI: 10.3934/biophy.2016.1.171
AIMS Biophysics 3/1 2019-07-24

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