This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 955756.

Research

Overview

The overarching aim of the Train2Target programme was to deliver leads for a new generation of innovative antibacterials to treat infections by multi-drug resistant pathogens. This has been achieved by exploiting the mechanisms that govern the growth of the outer membrane (OM) and a thin peptidoglycan (PG) layers and their coordination to highlight novel targets for antimicrobial discovery.
More particularly, the Train2Target network has been training over the last 4 years 15 Early Stage Researchers (ESRs) in all scientific and non-scientific aspects related to the drug discovery process, including the following:

  • Dissecting at the molecular level the function of the core envelope machineries
  • Investigating how the activities of envelope machineries are orchestrated and coordinated with PG synthetic machineries elongasome and divisome to ensure appropriate growth of the envelope layers during the cell cycle
  • Developing innovative screening strategies/ technologies to identify molecules inhibiting envelope biogenesis

Key Facts

Programme:
H2020-MSCA-ITN-2016 (ETN)

Duration:
01.01.2016-31.12.2020

Budget:
3.6 million euro

Factsheet: 

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Workplan

The T2T research programme is based on 3 scientific work packages (WPs) and 3 WPs dedicated to the training, the dissemination and management of the research results. Each of our 15 ESRs will focus on the research within one of these WPs while getting an insight into the other WPs as part of the network-wide scientific training workshops.
The University groups and the industry partners will contribute equally to the development of the research plan and to its excellence.

WP1

Molecular dissection of protein machineries that orchestrate envelope growth aimed to dissect at the molecular level the function of the Lpt and BAM envelope machineries by using interdisciplinary approaches based on an array of genetic, biochemical, biophysical and structural biology techniques. The assembly of Lpt and BAM machineries and the interaction with their substrates (LPS and OMPs, respectively) was crucial for their function and was an excellent target for inhibition.

WP2

Cross-talk between core envelope machineries during cell cycle addressed the coordination of envelope machineries. We explored how the Lpt and BAM machineries monitored the activities of the PG synthetic machineries (elongasome and divisome) to drive appropriate growth of the envelope layers.

WP3

New inhibitors of envelope biogenesis had been identified novel hits and leads targeting the envelope biogenesis process using different and complementary approaches exploiting the novelty of targets (envelope machineries and coordination) combined with innovation in the screening technology. A successful hits and leads identification relied not only on the novelty of the approaches, outlined in WP1 and WP2, but also on the consolidated expertise of the industrial partners in high-throughput screenings, hit identification and hit to lead drug discovery programmes.

Publications

List all the project publications in the Fold-out-section below.

  • Laguri, C. ; Sperandeo, P. ; Pounot, K. ; Ayala, I. ; Silipo, A. ; Bougault, C.M. ; Molinaro, A. ; Polissi, A. ; Simorre, J.P. (2017). Interaction of lipopolysaccharides at intermolecular sites of the periplasmic Lpt transport assembly. Scientific Reports, 7, 9715-1-9715–13. https://doi.org/10.1038/s41598-017-10136-0.
  • Laguri, C., Silipo, A., Martorana, A.M., Schanda, P., Marchetti, R., Polissi, A., Molinaro, A., Simorre, J.P. (2018) Solid State NMR Studies of Intact Lipopolysaccharide Endotoxin. ACS Chemical Biology 2018 13 (8), 2106-2113 DOI: 10.1021/acschembio.8b00271. 
  • Sperandeo, P.; Martorana, A.M.; Polissi, A. (2017). The lipopolysaccharide transport (Lpt) machinery : A nonconventional transporter for lipopolysaccharide assembly at the outer membrane of Gram-negative
    bacteria. J Biol Chem https://doi.org/10.1074/jbc.R117.802512.
  • Meiresonne, N. Y., Consoli, E., Mertens, L. M. Y., Chertkova, A., Goedhart, J., & den Blaauwen, T. (2018). Superfolder mTurquoise2ox optimized for the bacterial periplasm allows high efficiency in vivo FRET of cell division antibiotic targets. BioRxiv, 1–23. https://doi.org/10.1101/415174.
  • Peters K, Pazos M, Edoo Z, Hugonnet JE, Martorana A, Polissi A, VanNieuwenhze MS, Arthur M, Vollmer W. 2018. Copper inhibits peptidoglycan LD-transpeptidases suppressing b-lactam resistance due to by-pass of Penicillin-binding proteins. Proceedings of the National Academy of Sciences USA 115, 10786-10791.
  • Morè N, Martorana AM, Biboy J, Otten C, Winkle M, Gurnani Serrano CK, Monton Silva A, Atkinson L, Yau H, Breukink E, den Blaauwen T, Vollmer W and Polissi A. (2018) Peptidoglycan remodelling enables E. coli to survive severe outer membrane defect. mBio (in press).
  • Cleverley R, Ruttner Z, Rismondo J, Corona F, Tsui, HCT, Alatawi F, Daniel R, Haldebel S, Massidda O, Winkler M, Lewis R, (2019). The cell cycle regulator GpsB functions as cytosolic adaptor for multiple cell wall enzymes, Nat Commun 10, 261. https://doi.org/10.1038/s41467-018-08056-2.

Science slams

In case you have been wondering what each ESR has been researching within the Train2Target project they have created short videos to introduce their area of research. These videos have been created as part of the Train2Target Science Slams which aim to provide an educational resource to the general public and other interested audiences.

Project overview
ESR2 & ESR10

Drug discovery
ESR12

LPT Machinery
ESR1, ESR6 & ESR11

Introducing BAM
ESR7 & ESR9

Rcs system in Escherichia coli
ESR4 & ESR5

What are antibiotics? 
ESR15

Peptidoglycan 
ESR8 & ESR14

Drug discovery
ESR3

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