ESR project in INNOTARGETS

ERS1: Metabolic drug targets in Streptococcus suis

Recruitment by IRTA, Spain
PhD enrolment at Wageningen University, The Netherlands

The ESR enrolled in IRTA will study metabolic aspects of Streptococcus suis. S. suis is an important porcine pathogen, which requires frequent use of antibiotics to prevent high morbidity and mortality in intensive pig production. It is also an emerging zoonotic pathogen associated with sepsis and meningitis in humans. MDR has recently become a global concern in this bacterium. The ESR will characterize the metabolism of this strictly fermentative, Gram positive bacterium growing in a model for the natural host, the pig, using a transposon-based approach (TraDis or TnSeq) with a view to identify essential metabolic targets. The ESR will be supervised by Dr. Virginia Aragón from IRTA and co-supervised by Dr. Jerry Wells from Wageningen University, which will be the PhD awarding institution. In addition, the ESR will benefit from secondments at Wageningen University (The Netherlands) and at NAICONS (Italy). The ESR will also participate in network-wide training activities. 

Contact: Dr. Virginia Aragón virginia.aragon@irta.cat -

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ESR2: Re-sensitising drug resistant Streptococcus suis to antimicrobial treatment

Recruitment by Wageningen University, The Netherlands
PhD enrolment at Wageningen University, The Netherlands

Use of Transposon insertion sequencing (TnSeq) to identify genes which are essential for Streptococcus suis during infection and which increase sensitivity to antibiotics. 

Antimicrobial resistance (AMR) is a major challenge to human health and infections due to resistant bacteria are predicted to exceed cancer as the primary cause of human mortality by 2050, negatively impacting on world economy and social stability. Prudent use of antimicrobials can slow down the development of AMR, but it cannot solve the challenges caused by multi-drug resistant bacteria (MDR), some of which are resistant to all antimicrobials currently on the market.

Photo of lab workStreptococcus suis is a globally emerging zoonotic pathogen that occurs naturally in the upper respiratory tract, the genital, and the alimentary tract of pigs. S. suis is an important cause of invasive disease in pigs leading to increased use of antibiotics as prophylactic and metaphylactic interventions. S. suis is an emerging human pathogen in in South East Asia where it causes outbreaks of meningitis in humans leading to high mortality. The project will use transposon (Tn) mutagenesis and Tn insertion-sequencing of mutant libraries in Streptococcus suis to (i) identify genes required for in vivo survival during an infection and (ii) to identify gene mutants that sensitize MDR bacteria to existing antibiotics, including antimicrobial-resistant strains. These genes may also be relevant therapeutic targets for other pathogenic bacteria and will be used for structure-based drug discovery in collaboration with other academic and industrial partners in the project. The PhD candidate will work with molecular biology tools to generate Tn libraries in S. suis, in vivo mimicking models to identify conditional mutants, genetic and biochemical methods to characterise specific mutants, in silico methods and structural biology tools.

Contact: Professor Jerry Wells, jerry.wells@wur.nl

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ESR3: Metabolism of Staphylococcus aureus during systemic and skin infection

Recruitment by University of Sassari, Italy
Phd enrolment at University of Sassari, Italy

Staphylococcus aureus is an important human and animal pathogen, and so-called MRSA variants of this bacterium are on the WHO list of bacteria, for which novel drugs are urgently needed. The project will characterize the metabolism of an MRSA strain during systemic and skin infection with Staphylococcus aureus in mice using a random transposon approach (TraDis) to identify metabolic enzymes which are essential for growth in the host during the two types of infection. The position involves secondment to University of Copenhagen, Denmark for animal experimentation, and to the company NUREX (Italy) to study expression of metabolic enzymes in the host. The ESR will also participate in network-wide training activities. 

Contact: Professor Salvatore Rubino, rubino@uniss.it

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ESR4: In vivo proteome of Staphylococcus aureus during skin infection

Recruitment by Porto Conte Ricerche, Italy
PhD enrolment at University of Sassari, Italy

Staphylococcus aureus is an important human and animal pathogen, and multi-drug resistance is a challenge to treatment of infections. The project suggests that metabolic enzymes may be suitable targets for novel drugs. A proteomic approach will be used to characterize the changes in expression of metabolic enzymes during skin infection compared to growth in broth in the laboratory. Highly abundant proteins at the infection site compared to growth in broth will be assumed to be important for infections, and will be subjected to further characterization for their role during infection. The ESR will have a primary focus on so-called redundancy in the metabolism of Staphylococcus aureus, i.e. which metabolic enzyme systems constitutes back-up systems for each other during growth at the infection site, since this is important for selection of drug targets. Redundant enzymes will be identified using in silico approaches, and this part of the project will be carried out at Heinrich Heine University, Düsseldorf, Germany under supervision of Professor Oliver Ebenhoeh. The student will also spend time at the company NUREX (Italy) to study protein expression in the host. The ESR will also participate in network-wide training activities. Daniela Pagnozzi (PCR) is the supervisor and Professor Uzzau (UNISS) is the cosupervisor.

Contact: Dr. Daniela Pagnozzi, pagnozzi@portocontericerche.it

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ESR5. Modelling the metabolism of S. aureus in conjugation with the host

Recruitment by Heinrich Heine University, Düsseldorf, Germany
PhD enrolment at Heinrich Heine University, Germany

The candidate will develop a genome-scale metabolic model of Staphylococcus aureus. The basis for model development will be more than 50 fully sequenced and published genomes. The model will be interrogated with constraint-based techniques, such as Flux Balance Analysis (FBA), to answer relevant medical questions. These include the prediction of putative targets how metabolism of S. aureus can be interrupted without affecting the human host cells, for which reason the metabolism of host cells will also be considered. Moreover, available expression data will be integrated into the model to assess how metabolic activities change during the course of infection, and how it differs between different S. aureus clones. As part of the project, the student will carry out research at University of Copenhagen to validate model predictions, and he/she will further participate in development of in situ toxicity-prediction-tools during a visit to the pharmaceutical company, ABAC, Barcelona, Spain. The ESR will also participate in network-wide training activities. 

Contact: Professor Oliver Ebenhoeh, oliver.ebenhoeh@hhu.de

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ESR6. Re-sensitizing Methicillin resistant Staphylococcus aureus (MRSA) to beta-lactam antimicrobials

Recruitment by University of Sassari, Italy
PhD enrolment at University of Sassari, Italy

WHO have included MRSA (methicillin resistant Staphylococcus aureus) on the list of bacteria, for which novel antimicrobials and alternatives to antimicrobials are urgently needed. The ESR will identify enzymes, which are not part of the mecA-gene cassette, responsible for methicillin resistance in S. aureus, but which are newer-the-less essential for the expression of the resistance, using a random transposon approach. Genes encoding enzymes in this group will be further characterized for their role in expression of the resistance. Mobility between project partners is of high importance, and the candidate will carry out part of the project at University of Copenhagen, Denmark (transposon mutant work). In collaboration with the company NUREX (Italy), he/she will further study expression of selected genes and proteins in vivo. The ESR will also participate in network-wide training activities. 

Contact: Professor Salvatore Rubino, rubino@uniss.it

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ESR7: Antimicrobial Target identification by “omics-data”-guided analysis

Recruitment by Oxford Brookes University, UK
PhD enrolment at Oxford Brookes University, UK

You will be required to develop and refine existing metabolic models of E. coli, S. aureus and S. suis and analyse them in order to identify potential metabolic responses to antibiotic exposure, and to use these results to aid the design and interpretation of experimental studies. 

The multidisciplinary nature of the project means that you will liaise with all other ESRs in the team, travel to various meetings and workshops that are part of the training package. The post will also involve two periods of secondment (of approximately 2 moths duration) to the Department of Veterinary and Animal Sciences at the University of Copenhagen and with our industrial partner, ABAC Therapeutics in Barcelona. You will acquire complementary competences in specialised workshops, as well as through internships in other laboratories or with industrial partners within the network. 

The work will be carried out within the Cell Systems Modelling Group (http://mudshark.brookes.ac.uk) in the Department of Biological and Medical Sciences and supervised by Dr Mark Poolman.  

Contact: Dr. Mark Poolman, mgpoolman@brookes.ac.uk

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ESR8. Identification of metabolic reactions essential for spread of resistance plasmids

Recruitment by University of Copenhagen
PhD enrolment at University of Copenhagen

Plasmids play an important role in spread of antimicrobial resistance, and recent studies have shown that treatment with cephalosporin drugs may increase transfer of resistance plasmids in vivo. The project aims to determine the mechanisms behind this antibiotic induced conjugative spread of resistance-plasmids in Escherichia coli. It will identify genes and regulatory pathways that are involved in the increased frequency of resistance-plasmid transfer using molecular techniques. The project is carried out in collaboration with University of Sassari, Italy, and the ESR is expected to spend at least 2-3 months in the laboratories of the co-supervisor, Professor Salvatore Rubino, to carry out detailed characterization of mechanisms affecting the enhancement seen in plasmid transfer during treatment. Further, a screen for compounds, which can interfere with the increase in plasmid-transfer, will be carried out in collaboration with ABAC Therapeutics, Barcelona, Spain. The ESR will also participate in network-wide training activities.  

Contact: Associate professor Line E. Thomsen; email: leth@sund.ku.dk

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ESR9. E. coli secondary resistome to aminoglycoside treatment

Recruitment by University of Copenhagen
PhD enrolment at University of Copenhagen

Antimicrobial resistance in E. coli is a growing concern world-wide, and there is a need to increase our understanding of the responses in resistant bacteria to treatment with antimicrobial drugs. The project will identify how the metabolism of MDR E. coli changes in response to treatment with aminoglycoside drugs using a transposon based approach. Metabolic enzymes which appear particularly important for adaptation to growth in the presence of aminoglycosides will be further characterized using molecular technique. Changes in the metabolism during treatment will be determined using in silico approaches, and the ESR will have secondment to Brookes University, Oxford to carry out metabolic modelling. A screen for bioactive compounds with activity against selected metabolic enzymes will further be carried out in collaboration with the company, NAICONS (Italy). The ESR will also participate in network-wide training activities. 

Contact: Professor John Elmerdahl Olsen, jeo@sund.ku.dk

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ESR10. Re-sensitizing multidrug-resistant Escherichia coli to fosfomycin and macrolides

Recruitment by University of Copenhagen
PhD enrolment at University of Copenhagen

The project will identify non-essential proteins that are required to express acquired resistance to different antibiotics in E. coli using a random transposon approach. The resulting mutants will be characterized both in vitro and in vivo to assess whether the identified proteins and their associated metabolic pathways can be used as drug targets for restoring antimicrobial susceptibility. The project will be carried out in collaboration with a small enterprise in the field of drug discovery (NAICONS) and Oxford Brookes University, and the student will spend time working in the laboratories of these partners. 

Contact: Professor Luca Guardabassi, lg@sund.ku.dk

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ESR11. Identification of bioactive molecules with antimicrobial activity

Recruitment by Naicons, Italy

PhD enrolment at University of Copenhagen, Denmark

Antimicrobial resistance is a growing medical challenge, hampering the effectiveness of existing drugs and threatening the lives of patients. Therefore, there is a pressing need for compounds that re-sensitise drug-resistant bacteria to existing antimicrobials. To address this problem, the EU-funded INNOTARGETS project will train early-stage researchers in the identification of novel metabolic drug targets in pathogenic bacteria.

The project comes as a collaboration between academia and industry and will guide researchers to use innovative approaches to achieve their scientific goals. INNOTARGETS aims to provide ESRs with scientific and technical skills attractive to both industry and academia. ESRs will be equipped with complementary skills deemed important for research team leaders, will have an individual profile according to their own career dreams and will be capable of life-long self-directed learning. Each ESR will work closely together with 11 other ESRs in the INNOTARGETS network.

Contact: Dr. Stefano Donadio, sdonadio@naicons.com

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ESR12. Development and validation of in vitro tests, and algorithms to predict toxicity

Recruitment by ABAC, Spain
PhD enrolment at Heinrich Heine University, Düsseldorf, Germany

The project aims to develop and validation in vitro tests, computer tools, as well as to improve algorithms to determine and assess the toxicity of compounds that demonstrate antimicrobial activity. The goal will be to develop a tool to prioritize and select high quality Hits and Leads molecules that meet multiple developability criteria (weighted profile) and therefore increase the chances to identify robust candidates, reducing technical risk and maximize success to reach the market. During the project, the candidate will have secondments to Heinrich-Heine-Universitaet Düsseldorf, Germany to learn metabolic modelling, and at Institut de Recerca i Tecnologia Agroalimentaries (IRTA), Spain to test prediction from the tool on cell cultures. 

Contact: Dr. Domingo Gargallo-Viola, dgargallo@abactherapeutics.com

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