Thesis supervisor: Gyula Batta
Location of studies (in Hungarian): Chemistry building, rooms E-18 and B-13 Abbreviation of location of studies: E18
Description of the research topic:
Resistance of microorganisms against commercially available antibiotics and antifungal pharmaceuticals is growing and threatens with epidemics in the 21st century. We have a long research history in two topics:
first, the glycopeptide - or vancomycin type - antibiotics, that were considered as the last resort against some deadly gram-positive bacteria (superbugs). Some semisynthetic variants of the aglycons have antiviral effects (e.g. against HIV, Flue or Ebola). We study the mode of action of eremomycin and chloro-eremomycin in complex with bacterial cell-wall analogue peptides, and the oligomerisation states vs. binding affinity of these antibiotics in solution. To this end, analysis of NOESY spectra gives the 3D structure, while 15N and 13C NMR relaxation data leads to dynamics of the structures on the ps/ns timescale. In addition, NMR diffusion and DSC may report on the forming and disrupting of oligomers in solution, while ITC microcalorimetry might be applied to measure the binding affinity of peptide ligands or even with non-pathogenic bacterial cell wall extracts.
second, the antifungal disulfide miniproteins, that are potentially useful e.g. against Aspergillosis, that might cause fatal outcome in immunocompromised patients. These small proteins are produced by fungi, like Penicillium chrysogenum, have 50-60 residues, and their beta-barrel like structures are augmented with several covalent disulfide bonds. They are harmless for mammalian cells, however they selectively kill other fungal strains. We have successfully determined the tertiary structures of some representatives (PAF, pdb code: 2MHV, sfPAFB pdb code: 2NC2). However, their mode of action is unclear until now at a molecular level. PhD student on the project will be familiar with up to date multidimensional protein NMR techniques for assignment and evaluation of the spectra, that ultimately leads to the structures of new members of this protein family. Some protein expression work (wet lab) might be necessary, to produce stable isotope labelled proteins for NMR. The planned NMR conformational dynamics and unfolding studies may help to disclose hidden states for understanding the mode of action. In addition, search for interacting partnes will be carried out using bioinformatics, LC-MS and ITC screening with the lysates of sensitive non-pathogenic fungi.
Laboratory and equipment: we have Bruker AVANCE II.-500 and Bruker NEO-700 - prodigy NMR spectrometers, and a protein wet lab for protein expression work extended with microcalorimeters ITC-200 and automatic capillary VP-DSC from Microcal/Malvern.
Required language skills: English Number of students who can be accepted: 1
Deadline for application: 2018-02-16
2024. IV. 17. ODT ülés Az ODT következő ülésére 2024. június 14-én, pénteken 10.00 órakor kerül sor a Semmelweis Egyetem Szenátusi termében (Bp. Üllői út 26. I. emelet).
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