Outmanoeuvring multiple defences
Our battle against bad bacteria threatens to end in a defeat. The rise of AMR, where bacteria evolve to resist our attempts to annihilate them, means new drugs are desperately needed. While researchers have no problem coming up with new molecules that can bind to lethal bacterial targets, getting the drugs inside bacterial cells is one of the biggest stumbling blocks in antibiotic drug development. Gram-negative bacteria, uniquely troublesome bugs, are protected by two different membranes; you might find a drug that gets through one of the membranes only to find that it cannot breach the other. Once you find a molecule that can cross both membranes, these bacteria have another weapon up their sleeves in the form of efflux pumps, which literally pump the drug back out of the cell.
Tricking the bacteria with “Trojan horse” antibiotics
TRANSLOCATION discovered many features of the protective cell membranes that control the access and expulsion of compounds from bacteria. For example, several proteins contained in bacterial membranes are used by the organisms to gather food, and the research showed how bacteria might be fooled to allow entry of “Trojan Horse“ antibiotics which are designed to resemble such foods. TRANSLOCATION created new, sensitive methods to detect how much drug ends up inside the cell by means of counting molecules as they pass through single proteins. The team was able to quantify a whole range of membrane proteins at the atomic level and revealed the detailed structures of 40 different proteins involved in drug transport. They also developed new modelling approaches and a scoring function to predict permeability, which represents a loose set of “rules” about a drug’s likelihood to pass through membrane proteins.
The project partners also worked on creating a database, called the InfoCentre, that could link all the data that was generated from the different IMI AMR projects. Securing access to data and putting it together was very difficult, since every project tends to save data according to their own format and standards. This data gathering was part of another key feature of the project’s scope: learning from success and failure. It required a broad knowledge base, varying skill sets and a large body of data from multiple sources.
Legacy: a wealth of protein data, and a new company
Researchers who study molecules that can thwart the evolved protective mechanisms of bacteria will be able to use the work on proteins to help in their search for new antibiotics. The wider antibiotic research community will be able to access data from the results of all projects under the IMI AMR programme including that of TRANSLOCATION.
The experience gained from the development of the InfoCentre will contribute to IMI’s AMR Accelerator programme. Tools from the InfoCentre will form the basis of planned data and knowledge management systems to be used by multiple antibiotic discovery AMR Accelerator projects as they progress through to the clinic.
The Copenhagen-based company, GRIT42 which was founded during the TRANSLOCATION project, will help to support the day-to-day IT needs of AMR Accelerator projects and also aggregate suitable data sets. The data will be used to address complex scientific questions, such as which in-vivo models are best for testing new compounds, or how clinical trial design could be better informed by results from pre-clinical stages.
Such collaboration “impossible” in any other setting
In the area of early drug discovery, TRANSLOCATION solved a number of basic research questions from a much larger perspective compared to smaller nationwide research projects. The combination of skill sets and expertise, especially in bringing together biophysical and theoretical methods with more traditional microbiological approaches, was key to the success of TRANSLOCATION. Such close collaboration between competing pharmaceutical companies would have been impossible in any other setting. The partnership also made it easier to figure out the protocol for the collaborative relationship between the pharma companies and academic partners.
In order to make sure that the expertise generated by the project remains available, the project partners took advantage of the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR) to set up a virtual institute. In collaboration with experts from the European Open Screen network (EU-OPENSCREEN), the platform “Translocation-transfer” is now available. It can be used as a portal for the wider scientific community to access key experimental and computational tools established in TRANSLOCATION.
Translocation-transfer will establish a working model for these networks to collaborate and share essential know-how on theoretical and experimental methods for determining compound transport. This can then be integrated into the EU-OPENSCREEN compound profiling workflow for antibiotic programmes. The knowledge transfer process will be carried out through a series of tasks and workshops and facilitated by the New Drugs for Bad Bugs (NDD4B) InfoCentre platform. In the longer term, once these methods have been adopted by EU-OPENSCREEN, the data generated from screening projects specifically related to compound transport quantification will be released via the European Chemical Biology Database and ChEMBL database. The publicly-available data can then be used by the scientific community to improve our understanding of how molecular features mediate compound transport in bacteria, benefiting antibiotic drug discovery overall.