Biomolecular Analysis Research Topics
1) Nanospotter and confocal scanning analytics for discovery of antibiotics from nature.
Microfluidics spotter & confocal imaging scanner technologies will be combined and directed at the discovery and identification of new antibiotic drug candidates in complex natural extracts from tropical plants and from coral reef anemones, sponges, and other invertebrates. This project relies on a researcher with a background in analytical chemistry, biochemistry or pharmacochemistry. The project will combine the development of miniaturized analytical techniques (that require only very low sample amounts) with a screening campaign to discover new classes of antibiotics derived from nature.
2) Towards volatile antibiotics as inhaler drug candidates to treat pulmonary infections.
With this new technology one of our visions is to develop methods for screening organisms known to produce volatile antibiotics. Identification of these antibiotics might result in developing them further as inhaler administration type of drug candidates for pulmonary infections by bacteria such as tuberculosis and legionella. This project relies on a researcher with a background in analytical chemistry, biochemistry, food or plant chemistry. The project will combine the development of new analytical techniques that allow identification and purification of volatile antibiotic candidate molecules with screening biological sources that are known to produce volatile compounds with antibiotic properties such as plants and microbes.
To read more about these research topics, go to the Biomolecular Analysis page.
Structural Biology Research Topics
1) Understanding dormancy - combating bacteria that survive standard antibiotic treatment.
In response to antibiotic treatment some bacteria can down-regulate their metabolism and survive antibiotics in a hypo-metabolic state referred to as 'dormancy'. Bacteria in this dormant state are a major reason for long and complicated extensive antibiotic treatment, e.g. in case of tuberculosis. We aim at a better understanding of dormancy and investigate how dormancy can be overcome.
2) Exploiting bacterial survival factors as new, ‘hidden’ antibiotic targets.
New antibiotic targets are urgently needed to combat multi-drug resistant pathogenic bacteria. In our group we have identified a protein, cytochrome bd, that defends pathogenic bacteria against antibiotics and other stress factors. Inactivation of such a ’survival factor’ may significantly enhance the activity of a variety of antibiotics and therefore represent a new strategy in antibiotic development. We are interested in understanding the role of cytochrome bd and related ‘survival factors’ and aim at developing small-molecule inhibitors against this protein.
To read more about these research topics, go to the Structural Biology page.
Integrative Bioinformatics Research Topics
1) Unraveling the perturbation of GPCR signalling networks upon HCMV infection - implications for proliferative diseases.
Building upon Jacobsen et al, 2016 and Dinkla et al, 2014, we can identify key players in the HCMV US28 induced signalling network, affecting amongst others the WNT/b-Catenin signalling pathway. A thorough understanding of this signalling network, and how it is perturbed by the viral US28 GPCR, is one of the main bottlenecs in combatting HCMV.
The candidate should have a strong interest in computational approaches to network biology. Expertise in computational biology or graph algorithms, or a similar area, is an advantage.
To read more about these research topics, go to the Integrative Bioinformatics page.
Organic Chemistry Research Topics
1) Chemical stabilization of peptide secondary and tertiary structures.
To modulate the secondary structure of synthetic peptides, non-natural amino acids are introduced. The design process involves building block and solid-phase peptide synthesis as well as biophysical characterization of ligand-protein interactions applying e.g. protein crystallography and isothermal titration calorimetry. The ultimate goal is the identification of peptidomimetics that allow a targeting of protein so far considered “undruggable”.
To read more about these research topics, go to the Organic Chemistry page.
Systems Bioinformatics and Medicinal Chemistry Research Topics
1) Metabolism as a multi-parasite drug target with glucose transport as the selectivity handle.
All living cells need to maintain cellular homeostasis. Importantly, quantitative differences between cells will result in different weak points in their cellular networks. These network differences can be exploited to selectively target one cell type, leaving another unharmed. DifferentialMetabolic network analysis has revealed that ATP production in several parasites, e.g.Trypanosoma brucei, (African sleeping sickness) and Plasmodium falciparum (malaria) is extremely vulnerable to decreased uptake of glucose - a network vulnerability that is not shared by human red blood cells. Hence, these parasitic glucose transporters are excellent, network-selective drug targets.
In this project we aim at targeting the T. brucei glucose transporter TbrTHT1, expressed in the human-infective lifestage of the parasite. To this end, established glucose-uptake assays (both in trypanosomes and in yeast strains expressing the TbrTHT1 gene) will be employed to screen various (fragment-) libraries of small molecules. Hits will be tested in in vitro cultures of T. brucei for their killing effect. Moreover, structure-based homology modeling comparing the structure of the human glucose transporter GLUT1 with the inferred structures of parasite transporters will be used to complement the existing network-selectivity with structure-based drug design to come to potent and selective multi-parasite-targeting drugs.
Molecular Microbiology Research Topics
1) Targeted delivery of antimicrobials.
Using a synthetic biology approach we currently develop a method to decorate bacteria with proteins of choice. In a first step, (non-pathogenic) bacteria are modified to produce large amounts of a specific acceptor protein at their surface. In a second step, purified donor proteins are added to the decorated bacteria together with a novel super strong “protein glue”. The purified donor proteins are equipped with a specific peptide that is recognised by the glue and allows coupling of the donor protein to the acceptor protein. This way, any protein or even peptide-sugar hybrid can be used to decorate the bacteria and the potential applications are limitless.
We challenge the candidate to optimize this system and explore applications in the targeted delivery of antimicrobials. For instance, harmless bacteria could be decorated with antibodies directed against surface antigens of pathogenic bacteria. These “good bugs” that target “bad bugs” can in addition be modified to produce antibiotics or cytokines that modulate host immune responses. The resulting focused production at the site of infection is expected to be much more effective than systemic administration of antibiotics and immune modulating agents.
Depending on the exact project plans, multiple interactions with other AIMMS and VUmc groups are foreseen.
2) Targeting the Achilles’ heel of Gram-negative pathogens: Bam!
The recently discovered Bam protein complex plays a pivotal role in the biogenesis of the outer membrane that surrounds all Gram-negative bacteria. It forms the key machinery responsible for the insertion and assembly of outer membrane proteins. As such, it is also required for the biogenesis of bacterial surface factors, such as adhesins, relevant to virulence in a wide range of pathogens. In contrast to almost all other outer membrane proteins, two subunits of the Bam complex are essential for bacterial growth, while other subunits play important roles in membrane permeability and virulence. Together, these properties identify the Bam machinery as a novel prime target for antibiotic intervention. In addition, its strategic position in the outer membrane makes it highly accessible towards inhibitory compounds and insensitive to the action of drug efflux pumps.
In the previous antimicrobials program, a PhD student has successfully started the development of cell-based assays for high throughput screening of Bam inhibitors.
In a complementary approach, the present candidate will propose target based assays for instance making use of functional recombinant Bam complexes reconstituted in pure lipid vesicles. Given the recent flurry of publications showing high resolution structures of the Bam complex and its subunits, a structure based approach is also feasible, preferentially in collaboration with other AIMMS groups.
To read more about these research topics, go to the Molecular Microbiology page.