Molecular basis of the bacterial cell wall permeability


Start Date
End Date
IMI1 - Call 6
Grant agreement number

Type of Action: 
RIA (Research and Innovation Action)

IMI Funding
15 984 203
EFPIA in kind
8 135 833
5 634 118
Total Cost
29 754 154


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.

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.


Achievements & News

Could molecular vacuum cleaner be key to antibiotic effectiveness?
November 2017

Scientists from IMI’s Translocation project have uncovered the workings of a ‘molecular vacuum cleaner’ in the outer membrane of certain bacteria. The mechanism, described in a paper in Nature Microbiology, helps to keep the outside of the membrane free of clusters of molecules that could weaken it and the system could prove useful as a target for new antibiotics. ### Gram-negative bacteria like Escherichia coli are enclosed by two membranes which form a significant barrier for many antibiotics, limiting their effectiveness. The outer membrane is asymmentric; while the outside is coated in sugars that ward off many molecules that could be harmful to the bacteria, the inside is lined with phospholipids. Sometimes, phospholipids from the inside of the membrane accumulate on the outside. These clumps of phospholipids represent weak spots in the membrane, rendering it more vulnerable to toxic compounds like antibiotics. In this study, the scientists proposed a functional model of the ‘maintenance of lipid asymmetry’ (Mla) system, which removes phospholipids that have strayed into the outside of the membrane, sucking them back into the inside of the membrane where they belong. ‘Our three-dimensional structures and functional data show that MlaA forms a donut in the inner leaflet of the outer membrane. This binds phospholipids from the outer leaflet and removes these via the central channel, somewhat similar to a vacuum cleaner,’ explains Bert van den Berg of Newcastle University in the UK. ‘Our study illuminates a fundamental and important process in Gram-negative bacteria and is a starting point to determine whether the Mla system of Gram-negative pathogens could be targeted by drugs to decrease bacterial virulence, and to make various antibiotics more effective.’

Read more in the press releases from the University of Newcastle and Jacobs University

TRANSLOCATION in the spotlight in Science Translational Medicine 
April 2014

IMI’s TRANSLOCATION project is featured in an editorial in top science journal Science Translational Medicine. The editorial by Robert  Stavenger of GSK and Mathias Winterhalter of Jacobs University Bremen### is entitled How to get good drugs into bad bugs and looks more closely at the project’s aims and objectives. As one of several projects involved in IMI’s ND4BB platform, TRANSLOCATION is focused on addressing drug penetration into Gram-negative bacteria. 

ND4BB – the story so far, in Nature Reviews Microbiology
April 2014

IMI’s antimicrobial resistance (AMR) programme New Drugs for Bad Bugs (ND4BB) is the focus of a recent comment piece in Nature Reviews Microbiology by John Rex of AstraZeneca, who is involved in ND4BB.### The article explains how IMI and other projects around the world are tackling the biggest challenges in antibiotic research and development. For example, TRANSLOCATION is investigating how to transport antibiotics into bacteria, while COMBACTE focuses on the design and implementation of more efficient clinical trials. ENABLE, IMI’s newest AMR project, is creating a drug discovery platform to fast-track the development of promising molecules. The article also highlights IMI project RAPP-ID, which is working on point-of-care tests, as well as a number of US-based initiatives. Looking to the future, the article notes that IMI has a project in development which will investigate new business models and economic strategies to incentivise the development of new antibiotics.

The article concludes: ‘Although the [AMR] crisis is far from resolved, the leadership of the European Commission are to be commended for their far-sighted approach to creating ND4BB and its projects, all of which provide hope that the global community will have access to an adequate pipeline of novel antimicrobial agents with which to address the challenge of AMR.’

Antimicrobial resistance projects sign memorandum of understanding
December 2013

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.

Participants Show participants on map

EFPIA companies
  • Astrazeneca AB, Södertälje, Sweden
  • Basilea Pharmaceutica International AG, Basel, Switzerland
  • Glaxosmithkline Research And Development LTD., Brentford, Middlesex, United Kingdom
  • Janssen Pharmaceutica Nv, Beerse, Belgium
  • Sanofi-Aventis Recherche & Developpement, Chilly Mazarin, France
Universities, research organisations, public bodies, non-profit groups
  • Assistance Publique - Hopitaux De Paris, Paris, France
  • Centre National De La Recherche Scientifique Cnrs, Paris, France
  • Fraunhofer Gesellschaft Zur Foerderung Der Angewandten Forschung E.V., München, Germany
  • Fundacion Privada Instituto De Salud Global Barcelona, Barcelona, Spain
  • Jacobs University gGmbH, Bremen, Germany
  • Johann Wolfgang Goethe-Universitatfrankfurt Am Main, Frankfurt am Main, Germany
  • Société civile SYNCHROTRON SOLEIL, GIF-sur-YVETTE CEDEX, France
  • The University Court of the University of St Andrews, St Andrews, Fife, United Kingdom
  • Universitaetsklinikum Freiburg, Freiburg, Germany
  • Universitat Basel, Basel, Switzerland
  • Universite D'Aix Marseille, Marseille, France
  • Universite De Geneve, Genève 4, Switzerland
  • University College Dublin, National University Of Ireland, Dublin, Dublin, Ireland
  • University Of Newcastle Upon Tyne, Newcastle upon Tyne, United Kingdom
  • Università di Cagliari, Cagliari, Italy
Small and medium-sized enterprises (SMEs)
  • GRITsystems A/S, Dragør, Denmark
  • Ionovation GmbH, Osnabrück, Germany
  • Nanion Technologies GmbH, München, Germany
  • The Hyve BV, Utrecht, Netherlands
  • Yelen, Ensues La Redonne, France
Non EFPIA companies
  • Bruker Daltonik GmbH, Bremen, Germany


Project coordinator
Robert Stavenger
United States
+1 610 917 7163
Managing entity
Mathias Winterhalter
Jacobs University gGmbH