ESR Projects and Fellows – University of Copenhagen

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Projects

Short descriptions of ESR projects (links to full descriptions are soon to come)

ESR1: Computational Models of Histidine Kinases and their Inhibitors

(Oxford Drug Design, Limited) Based at Oxford Drug Design in the UK, working with a small group of computational and drug-discovery experts, this project will use a combination of proprietary and commercial modelling tools to understand the interactions of these bacterial proteins and their ligands.  The models will be used to design improved inhibitors and to enhance their use as antibacterial compounds.  For details, see https://www.oxforddrugdesign.com/careers.html

ESR2: Structural and functional characterization of histidine kinase-inhibitor complexes

(Agencia Estatal Consejo Superior De Investigaciones Cientificas) The PhD candidate will focus on the rational design of novel inhibitors of histidine kinase with antibiotic activity using a multidisciplinary approach that includes (but is not limited to) molecular biology, biochemistry and biophysical techniques. The structural characterization of the drug-histidine kinase complexes by X-ray crystallography will be the starting point for the design of new inhibitors with greater potency and selectivity, which will be analysed biochemically and biophysically by the candidate. For further information, please contact Alberto Moreno, at amarina@ibv.csic.es.

ESR3: Chemical synthesis of new two-component system inhibitors

(Latvijas Organiskas Sintezes Institutes) ESR3 will be involved in synthesis of new inhibitors designed to target two component signal transduction systems in bacteria of relevance to bacterial viability and virulence.

ESR4: In vitro and in vivo characterization of inhibitor antibacterial activity and cytotoxicity (WU (CSIS))

The person will work in an international team with 3 other PhD students using a structure-based drug discovery and development approach to improve the potency and selectivity of several small molecule inhibitors.  The research involves: (i) selecting histidine kinase targets involved in virulence and testing their enzymatic inhibition by newly discovered inhibitors, (ii) demonstrating selective target inhibition in live bacteria, (iii) testing therapeutic potential for antibiotic resistant bacterial pathogens and (iv) testing for potential host cytotoxicity. For further information, please contact Jerry Wells, Wageningen University, at jerry.wells@wur.nl.

ESR5: Novel sources of microbial diversity for new antibiotics

(Naicons/Wageningen University).
Within antibacterial drug discovery the aim of the project is to devise methods to enhance production of bioactive metabolites in Naicons’ large collection of actinomycetes. Novel compounds with antibacterial activity will be isolated and to their structure elucidated. The selected candidate will be employed with a three-year contract by Naicons (Milan, Italy), where he/she will perform most of the research work. He/she is expected to perform part of the research work at secondment institutions and to register for a PhD programme at the Wageningen University, NL.

ESR6: Ecological approaches to habitat exploitation for natural antimicrobial discovery

(University of Warwick) ESR6 will exploit current ecophysiological knowledge to explore the distribution and diversity of potential bioactive molecules found in natural habitats and will use metagenomes from a range of habitats with a focus on soils to identify such bioactive compounds. Novel approaches will be taken to express regulate gene cluster in super hosts and evaluate production physiology in vitro and in situ. Structure of the expressed natural products will be elucidated and mode of action assessed. Link to position will soon be posted. For further information, please contact Liz Wellington, Warwick University, at e.m.h.wellington@warwick.ac.uk.

ESR7: Microbiota encoded antimicrobials against Streptococcus suis (WU (SFR-partner))

In complex biological systems, small molecules often mediate microbe-microbe and microbe-host interactions. The research builds on recent results showing that specific bacterial strains in the tonsil and upper respiratory microbiota possess biosynthetic gene clusters that produce inhibitors of pathogenic S. suis, which occupies the same ecological niche. A culturomics approach will be combined with a culture-dependent robotic screens to identify commensals producing peptide or small molecule inhibitors of S. suis. Genome sequencing of antimicrobial producing isolates and purification / mass-spectrometry will be used to identify and structurally characterize novel antimicrobial compounds. Commensals antagonizing a broad range of S. suis strains will be tested for their capacity to colonize and prevent colonization of pigs by S. suis in the vulnerable weaning period. Link to position will soon be posted. For further information, please contact Jerry Wells, Wageningen University, at jerry.wells@wur.nl.

ESR8: Antimicrobials from human and animal microbiomes

(Statens Serum Institut)
ESR8 will combine big data including microbiome, metagenome and genome data, bioinformatics and laboratory work to identify new antimicrobials from nature. It is an ambitious project that involves identifying candidate species from both human and animal hosts that produce antibacterials against pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus suis. In vitro activity against S. aureus will be examined to determine new antimicrobials expressed by these bacteria and additionally explored will be microbiota analysis of pig-colonizing bacteria to identify bacteria that potentially generate specific antibacterials that prevent or kill MRSA or S. suis.

ESR9: Intrinsic resistance to antibiotics

(University of Copenhagen)
Bacterial pathogens are naturally resistant to some antibiotics and resistance levels vary between strains. ESR9 will examine the “intrinsic resistome” formed by common bacterial genes influencing resistance of Staphylococcus aureus, MRSA and other resistant strains. This knowledge will provide a basic understanding of antibiotic resistance and may lead to new antimicrobial strategies enabling the use of already approved antibiotics against untreatable, antibiotic resistant pathogens.

ESR10: Potentiation of current antimicrobials

(University of Copenhagen)
ESR10 will identify novel substances with antimicrobial activity or the ability to potentiate current antimicrobials in an established library of microbial extracts, using hypomorphic expression of essential and non-essential genes of multi-drug resistant Klebsiella pneumonia and ESBL Escherichia coli. This will allow detection of compounds at the collaborating partner, Naicons, Italy with low abundance or specificity to the target protein, enhancing identification of new antibiotic scaffolds or hits. Link to position will soon be posted. For further information, please contact John Elmerdahl Olsen, University at Copenhagen, at jeo@sund.ku.dk.

ESR11: Phage therapy against antibiotic resistant E. coli

(Ghent University)
ESR 11 will target E. coli infections and antibiotic resistant E. coli with phage therapy and decipher what elements, both bacterial and phage related that are involved in this host specificity and to use them to make a concise cocktail that has a broad spectrum in treating E. coli infections in different animal species. 

ESR12: Phages in virulence and transmission of antibiotic resistance

(University of Copenhagen)
Phages are viruses that can enhance virulence and transfer mobile genetic elements in bacterial cells. For the human pathogen S. aureus, phages contribute to colonization of humans and also to the transfer of antibiotic resistance between strains. In this project, the candidate will study transfer of the humanizing phage phi13 to livestock MRSA strains and examine how transduction and auto-transduction contribute to development of antibiotic resistance. Link to position will soon be posted.

ESR13: Tackling resistance gene transmission in farms

(Universidad Complutense de Madrid)
ESR13 will identify antibiotic combinations and biocides that interfere with both, plasmid transfer and plasmid stabilization in bacteria of relevance to the animal production. Also, the candidate will test the combination of antibiotics that reduces plasmid transfer and stabilization in an in vivo model of antibiotic resistance transfer. Experiments will determine the genetic basis of plasmid transfer and stabilization and will point to solutions that may minimize resistance gene transfer. For further information, please contact Bruno Gonzalez, Complutense University, at cartnetmadrid@ucm.es.

For further information, please consult the CARTNET website https://cartnet.ku.dk/, or contact project coordinator, Professor Hanne Ingmer, University of Copenhagen: hi@sund.ku.dk.