INTEGRATE Work Packages

INTEGRATE ETN Scientific Coordinator: This email address is being protected from spambots. You need JavaScript enabled to view it., University of Parma

Infections from Gram-negative bacteria have always posed a serious risk to public health, and all the more so in recent years with the inexorable rise in resistance against commonly-prescribed antibiotics such as fluoroquinolones, carbapenems, cephalosporins and aminoglycosides. As a result, therapeutic options for multi-resistant Gram-negative pathogens are becoming increasingly limited. Each year in the EU, multidrug-resistant bacterial infections result in the death of ca. 25,000 patients, with further healthcare costs and productivity losses estimated to be at least EUR 1.5 billion. Therefore, there is an urgent need for better antibiotic stewardship and for the discovery and development of new drugs to fight against Gram-negative bacteria.

INTEGRATE is a multidisciplinary Marie Curie Educational Training Network (ETN) consortium funded by the EU Horizon 2020 Programme. Our member teams will collaborate closely in the development of novel antibacterial approaches directed at emerging Gram-negative targets.

The targets for most of the conventional antibacterials are essential gene products, such as those involved in bacterial cell wall biosynthesis, protein synthesis, or DNA replication. Consequently, there is a very strong evolutionary selection pressure for resistance to arise against such compounds (and perhaps more importantly, for resistance to spread within the microbial population). This phenomenon, coupled with a widespread misuse of antibacterials, has given rise to bacteria that are simultaneously resistant to all available antibiotics. It is now accepted that identification of novel drug targets and non-conventional mechanisms, as well as the development of novel chemotypes is central to the fight against bacteria generally, and against Gram-negative bacteria in particular. 

An alternative approach is to not kill the bacteria, but instead, to attenuate their fitness. The rationale behind this emerging concept, which is attracting increasing interest from many sectors, is that by attenuating bacterial fitness the host immune system will be given a greater window of opportunity in which to clear the infection. Although we do not envisage that such approaches would ever completely replace “conventional” antibiotic treatment, they certainly have the potential to complement/synergize these (see Allen et al. “Targeting virulence: Can we make evolution-proof drugs?” for a recent commentary). The main scientific objective of INTEGRATE is to further validate this concept by developing, in a truly multidisciplinary context, a series of low molecular weight (LMW) inhibitors that are able to block or dysregulate pathways important for fitness. Through a seamless interaction of Work Package (WP)1, WP2, and WP3, the INTEGRATE consortium will characterize and validate a selection of key biological targets for the development of novel antimicrobial compounds. Some of these (such as DNA gyrase) are already established/proven drug targets, while others (ClpP, the glyoxylate shunt and enzymes of sulfur metabolism) are attracting increasing interest as alternatives to the conventional targets. Others still are known to be important (biofilm formation and quorum sensing), but have yet to yield good hits or proven MoA data in compound screening programmes.

Work Package 1: Computer Aided Molecular Design (WP leader: Antti Poso, University of Eastern Finland)
WP1 has the objective of carrying out ‘in silico’ virtual screening against selected targets in order to find structurally diverse hit compounds. A second aim of WP1 is to support individual hit optimisation projects developed under WP2.

Work Package 2: Medicinal Chemistry (WP leader: Danijel Kikelj, University of Ljubljana)
The main aim of this work package will be to coordinate and exploit the medicinal and synthetic organic chemistry activities directed to the design and synthesis of low molecular weight compounds to be evaluated as potential Gram-negative antibacterial agents.

Work Package 3: Molecular Microbiology and Bioactivity Screening (WP leader: Martin Welch, University of Cambridge)
The overall aims of WP3 are (a) to characterize and validate new or emerging targets for antimicrobial intervention, (b) to characterize the impact of novel low molecular weight (LMW) compounds on a previously-validated target, and (c) to provide enabling technologies that facilitate facile HTP screening, MoA, resistance mechanism(s) and in vivo validation of LMW compound hits.

Work Package 4: Training and Disemination (WP leader: Gabriele Costantino, University of Parma)
Main objectives of WP4 is to coordinate and direct the training through research and training education activities, to promote transfer of knowledge, to contribute to S&T and complementary training, and to disseminate project output.

Work Package 5: Management (WP leader: University of Helsinki)
Main objectives of WP5 are to coordinate and manage the execution of the INTEGRATE ETN.

Integrate-etn.eu

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska Curie grant agreement No  642620
European Union