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TRANSLOCATION

Molecular basis of the bacterial cell wall permeability

Summary

As part of the IMI antimicrobial resistance (AMR) programme New Drugs for Bad Bugs, TRANSLOCATION aims to increase the overall understanding of how to get antibiotics into multi-resistant Gram-negative bacteria such as Escherichia coli and Klebsiella pneumoniae and how to stop the bacteria from ejecting the drug. In sharing the knowledge and data discovered, TRANSLOCATION will develop guidelines for designing and developing new drugs to tackle antibiotic resistance and create an information centre for pre-existing and on-going antibacterial research data which will be used to establish best practices for future antibacterial drug discovery efforts.

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The AMR arms race – developing New Drugs for Bad Bugs
AMR represents a serious and growing threat to human and animal health worldwide. According to the World Health Organization (WHO), ‘antibiotic resistance is becoming a public health emergency of yet unknown proportions’. In the EU, AMR is responsible for some 25 000 deaths every year, and the annual treatment and social costs have been estimated at some €1.5 billion. Meanwhile, new forms of resistance continue to arise and spread, leaving clinicians with few weapons to bring infections under control. Yet despite the recognised need for new antibiotics, the reality is that only two new classes of antibiotics have been brought to the market in the last three decades.

The reasons for this are manifold. On the scientific front, there is an urgent need for a greater understanding of how antibiotics work, how bacteria develop resistance to them, and what molecular mechanisms could be exploited to get round bacterial defence mechanisms. At the same time, today’s regulatory pathways mean clinical trials for antibiotics are extremely expensive. This, combined with the likelihood that the use of new antibiotics may be limited to situations where they are truly needed, leads to a low overall return on investment. Thus antibiotic discovery and development is simply no longer a financially viable option for businesses, and just a handful of pharmaceutical companies remain in the field.

If no action is taken to address these issues, we risk leaving society in a situation where doctors will have few, if any, options to treat resistant bacterial infections. To avoid a public health emergency, the entire antibiotic research community, including researchers in universities, small and medium-sized enterprises (SMEs), and pharmaceutical companies must work together to reinvigorate research into new antibiotics. As a public-private partnership (PPP), IMI is the ideal platform to launch such an initiative.

In its Action Plan against the rising threats from Antimicrobial Resistance of November 2011, the European Commission called for ‘unprecedented collaborate research and development efforts to bring new antibiotics to patients’ by, among other things, launching an IMI programme ‘for research on new antibiotics aimed at improving the efficiency of research and development of new antibiotics through unprecedented open sharing of knowledge’.

The result is the New Drugs for Bad Bugs (ND4BB) programme, the first two topics of which were launched as IMI’s 6th Call for proposals in May 2012. TRANSLOCATION is the result of one of those topics. A third topic under ND4BB was launched as part of IMI’s 8th Call for proposals in December 2012.

From single molecule translocation to rational drug design
The TRANSLOCATION project will focus on discovering important new information to improve the selection and optimisation of promising molecules which can be used for novel antibiotic drug discovery. The lack of progress in antibacterial drug discovery, especially against Gram-negative pathogens, is partly due to a lack of information about how potential drugs are able to get through the bacterial cell envelope and remain inside long enough to destroy it. Through this new research, TRANSLOCATION will generate knowledge which can be used in the development of new technologies for measuring the transport of molecules across the cell envelope into the bacteria, and for better understanding the mechanisms that bacteria use to flush out certain molecules before they can be effective. Experts will research the structures of porins, proteins which act as portals in the outer membrane of the bacteria for the transport of certain smaller molecules into and out of the bacteria.. Scientists from academia and industry will conduct a screening programme to identify key proteins which are important in understanding bacteria’s ability to reject certain molecules.

Learning from success and failure
This second key aspect of the project’s scope, learning from success and failure, requires broad knowledge and skill sets and a large body of data from multiple sources. The creation of a cross-project ND4BB information centre and the development of the business model to support the sharing of data will offer the wider antibiotic research community the opportunity to have access to new data from the results of all projects under the IMI AMR programme. TRANSLOCATION’s information centre will be managed through its newly-developed model for data sharing. The project team will coordinate the disclosure and combined analysis of previously confidential information, which is being provided primarily from participating EFPIA companies. Crucially, their data on historical successes and failures in antibacterial research and development allows a more streamlined approach to antimicrobial drug development and will help to speed up the drug discovery process by making it more efficient. Additionally, the TRANSLOCATION project will help coordinate the dissemination of information and knowledge from this and all other topics initiated under IMI’s ND4BB programme.

Discovery and efficiency will bring a boost to drug development for antibacterials
In this project a large number of small and previously separate research problems are combined allowing for synergy and understanding of how antibiotics move in and out of cells on a new and innovative level. This collaboration will bring together the antibacterial know-how of industry and leading academics with expertise in microbiology, biophysics and computational and structural biology to provide a holistic view of the problem and a novel approach to deliver advances in this challenging area. TRANSLOCATION will help close the gap between the burden of infections due to multidrug-resistant bacteria and the development of new antibiotics to tackle the problem.

 

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Achievements & News

Antimicrobial resistance projects sign memorandum of understanding
IMI’s first antimicrobial resistance projects, COMBACTE and TRANSLOCATION, have signed a Memorandum of Understanding (MoU) to facilitate their collaboration. The projects are part of ###the New Drugs for Bad Bugs (ND4BB) programme. As such, there was always an understanding that the projects would work together – this MoU simply formalises and sets out the framework for collaboration. Specifically, the MoU covers issues such as data sharing (and confidentiality), communication and coordination, as well as the creation of a shared Ethics Committee. One of the tasks of the TRANSLOCATION project is the creation of an Info Centre that would gather data from all ND4BB projects. With this in mind, the MoU also contains a section devoted to data standards and analysis. Looking to the future, the new ND4BB projects that will be set up in the coming months will also be invited to join the MoU.
(December 2013)

Participants

EFPIA member companies

  • AstraZeneca AB, Sweden
  • Basilea Pharmaceutica AG, Switzerland
  • Glaxosmithkline Research and Development Ltd, United Kingdom
  • Janssen Infectious Diseases – Diagnostics BVBA, Belgium
  • Sanofi-Aventis Research and Development, France
     

Non EFPIA company

  • Bruker Daltonik GmbH, Germany
     

Universities, research organisations, public bodies, non-profit groups

  • Assistance Publique - Hôpitaux de Paris, France
  • Centre National de la Recherche Scientifique, France
  • Société Civile Synchrotron SOLEIL, France
  • Fundacio Centre de Recerca en Salut International de Barcelona, Spain
  • Jacobs University Ggmbh, Germany
  • Johann Wolfgang Goethe Universität Frankfurt am Main, Germany
  • University of St Andrews, United Kingdom
  • Universita degli Studi di Cagliari, Italy
  • Universität Basel, Switzerland
  • Universitätsklinikum Freiburg, Germany
  • Université d'Aix-Marseille, France
  • Université de Genève, Switzerland
  • University College Dublin, Ireland
  • University of Newcastle upon Tyne, United Kingdom
     

Small and medium-sized enterprises (SMEs)

  • European Screening Port GmbH, Germany
  • Ionovation GmbH, Germany
  • Nanion Technologies GmbH, Germany
  • Nanospot GmbH, Germany
  • Yelen, France

 

Facts & Figures

Start Date 01/01/2013
Duration 60 months
   
Contributions
IMI Funding 15 984 203
EFPIA in kind 8 135 833
Other 5 207 970
Total cost 29 328 006

 

Links and Documents

IMI Funding per participant

Contact

Project Coordinator
Robert A. Stavenger

GlaxoSmithKline
Tel.: +1 610-917-7163
E-mail: Robert.A.Stavenger[AT]gsk.com

Managing Entity
Mathias Winterhalter

Jacobs University Bremen
Tel.: +49 421 200 3248
E-mail: m.winterhalter[AT]jacobs-university.de