Offene Stellen Bachelor-, Diplom- und Masterarbeiten

Projects for Bachelor-, Diploma- and Master-Thesis

Research group E.C. Böttger

The ribosome is the essential macromolecular complex of protein synthesis in all living cells. Ribosomes translate the genetic information encoded in messenger RNA (mRNA) into correct amino acid sequences. In the decoding site of the small ribosomal subunit, the mRNA codons are coupled with anticodons of cognate transfer RNA (tRNA). In the peptidyl transferase center (PTC) of the large ribosomal subunit, peptide bonds between the incoming amino acids and the growing peptide chain are formed. These steps in translation are efficiently inhibited by small molecules that bind to rRNA, some of which are used as antibiotic compounds in anti-infective therapy.

We use genetic techniques for introduction of defined mutations to investigate ribosome structure-function relationships at a molecular level, to study the determinants of antibiotic selectivity, to characterize the specificity of ribosomal inhibitors available and of future compounds to come, and to address the mechanisms of drug-associated toxicity. In collaboration with ETH and WSU we have started a drug development program by combining molecular genetics with chemical synthesis, i.e. genetic mutants guide the synthesis of novel aminoglycoside compounds with the view to develop derivatives with altered drug-target interaction. More recently, we have developed a strong interest in studying the donwstream effects of mistranslation in higher eukaryotes.

References (selected)

  1. XBP1 mitigates aminoglycoside-induced endoplasmic reticulum stress and neuronal cell death.
    Oishi N., Duscha S., Boukari H., Meyer M., Xie J., Wei G., Roschitzki B., Böttger E.C., Schacht J.
    submitted for publication
  2. Identification and evaluation of improved 4’-O-(alkyl) 4,5-disubstituted 2-deoxystreptamines as next generation aminoglycoside antibiotics.
    Duscha S., Boukari H., Shcherbakov D., Salian S., Silva S., Kendall A., Kato T., Vasella A., Böttger E.C.
    mBio 2014, 5: e01827-14
  3. 4’-O-substitutions determine selectivity of aminoglycoside antibiotics.
    Perez-Fernandez D., Shcherbakov D., Matt T., Leong N.C., Kudyba I., Duscha S., Boukari H., Pathak R., Dubbaka S.R., Lang K., Meyer M., Akbergenov R., Freihofer P., Vaddi S., Thommes P., Ramakrishnan V., Vasella A., Böttger E.C.
    Nature Comm. 2014, 5: 3112
  4. Spectinamides: a new class of semisynthetic antituberculosis agents that overcome native drug efflux.
    Lee R.E., Hurdle J.G., Liu J., Bruhn D.F., Matt T., Scherman M.S., Vaddady P.K., Zheng Z., Qi J., Akbergenov R., Das S., Madhura D.B., Rathi C., Trivedi A., Villellas C., Lee R.B., Rakesh, Waidyarachi S.L., Sun D., McNeil M.R., Ainsa J.A., Boshoff H.I., Gonzalez-Juarrero M., Meibohm B., Böttger E.C., Lenaerts A.J.
    Nature Med. 2014, 20: 152-158
  5. Importance of the 6'-hydroxy group and its configuration for apramycin activity.
    Mandhapati A.R., Shcherbakov D., Duscha S., Vasella A., Böttger E.C., Crich D.
    Chem. Med. Chem. 2014, 9: 2074-2083
  6. Synthesis, antiribosomal and antibacterial activity of 4’-O-glycopyranosyl paromomycin aminoglycoside antibiotics.
    Chen W., Matsushita T., Shcherbakov D., Boukari H., Vasella A., Bötger E.C., Crich D.
    Med. Chem. Comm. 2014, 5: 1179-1187
  7. In-vivo efficacy of apramycin in murine infection models.
    Meyer M., Freihofer P., Scherman M., Teague J., Lenaerts A., Böttger E.C.
    Antimicrob. Agents Chemother. 2014, 58: 6938-6941
  8. Dissociation of antibacterial activity and aminoglycoside ototoxicity in the 4-monosubstituted 2-deoxystreptamine apramycin.
    Matt T., Ng C.L., Lang K., Sha S.H., Akbergenov R., Shcherbakov D., Meyer M., Duscha S., Xie J., Dubbaka S.R., Perez-Fernandez D., Vasella A., Ramakrishnan V., Schacht J., Böttger E.C.
    Proc. Natl. Acad. Sci. USA 2012, 109: 10984-10989
  9. Structure-activity relationships among the kanamycin aminoglycosides: role of ring I hydroxy and amino groups.
    Salian S., Matt T., Akbergenov R., Harish S., Meyer M., Duscha S., Shcherbakov D., Bernet B.B., Vasella A., Westhof E., Böttger E.C.
    Antimicrob. Agents Chemother. 2012, 56: 6104-6108
  10. Genetic reconstruction of protozoan rRNA decoding sites provides a rationale for paromomycin activity against Leishmania and Trypanosoma.
    Hobbie S.N., Kaiser M., Schmidt S., Shcherbakov D., Janusic T., Brun R., Böttger E.C.
    PloS Negl. Trop. Dis. 2011, 5: e1161
  11. Molecular basis for the selectivity of antituberculosis compounds capreomycin and viomycin.
    Akbergenov R., Shcherbakov D., Matt T., Duscha S., Meyer M., Wilson D.N., Böttger E.C.
    Antimicrob. Agents Chemother. 2011, 55: 4712-4717
  12. Genetic analysis of interactions with eukaryotic rRNA identify the mitoribosome as target in aminoglycoside ototoxicity.
    Hobbie S.N., Akshay S., Kalapala S.K., Bruell C.M., Sherbakov D., Böttger E.C.
    Proc. Natl. Acad. Sci. USA 2008, 105: 20888-20893
  13. Mitochondrial deafness alleles confer misreading of the genetic code.
    Hobbie S.N., Bruell C.M., Akshay S., Kalapala S.K., Scherbakov D., Böttger E.C.
    Proc. Natl. Acad. Sci. USA 2008, 105: 3244-3249
  14. Engineering the rRNA decoding site of eukaryotic cytosolic ribosomes in bacteria.
    Hobbie S.N., Kalapala S.K., Akshay S., Bruell C., Dabow S., Vasella A., Sander P., Böttger E.C.
    Nucleic Acids Res. 2007, 35: 6086-6093
  15. Binding of neomycin-class aminoglycoside antibiotics to mutant ribosomes with alterations in the A-site of 16S rRNA.
    Hobbie S.N., Pfister P., Bruell C., Sander P., François B., Westhof E., Böttger E.C.
    Antimicrob. Agents Chemother. 2006, 50: 1489-1496
  16. A genetic model to investigate drug-target interactions at the ribosomal decoding site.
    Hobbie, S.N., Bruell C., Kalapala S., Akshay S., Schmidt S., Pfister P., Böttger E.C.
    Biochimie 2006, 88: 1033-1043
  17. Mutagenesis of 16S rRNA C1409-G1491 base pair differentiates between 6'OH and 6'NH3+ aminoglycosides.
    Pfister P., Hobbie S., Bruell C., Corti N., Vasella A., Westhof E., Böttger E.C.
    J. Mol. Biol. 2005, 346: 467-475
  18. 23S rRNA base pair 2057-2611 determines ketolide susceptibility and fitness cost of the macrolide resistance mutation 2058>>G.
    Pfister P., Corti N., Hobbie S., Bruell C., Zarivach R., Yonath A., Böttger E.C.
    Proc. Natl. Acad. Sci. USA 2005, 102: 5180-5185
  19. Analysis of the contribution of individual substituents in 4,6 aminoglycoside-ribosome interaction.
    Hobbie S.N., Pfister P., Bruell C., Westhof E., Böttger E.C.
    Antimicrob. Agents Chemother. 2005, 49: 5112-5118

Task description
Molecular biology, genetics, bioinformatics, biochemistry, and – depending on the applicant’s interest – structural biology.

Requirements
We are a young and dynamic work group offering a highly collaborative work environment in interdisciplinary fields of medical biosciences. We are looking for proactive and motivated students who are willing to make a significant contribution to the ongoing research projects.

Contact
Dr. Dimitri Scherbakov
dscherbakov@imm.uzh.ch
+41 44 634 26 72

Prof. Dr. Erik C. Böttger
boettger@imm.uzh.ch

Research group P. Sander

Mycobacterium tuberculosis, the causative agent of tuberculosis, is responsible fort two million deaths annually. M. tuberculosis has a unique lifestyle: it resides and multiplies in host cells equipped to efficiently kill other bacteria – the macrophages. In macrophages, the pathogen arrests phagosome maturation – which is thought to be important for its intracellular survival. The emergence of drug resistant strains, the absence of an efficient vaccine and the long lasting therapy (> 6 months) indicates an urgent need for an improved understanding of the biology of M. tuberculosis. Our research focuses on i) mechanisms of M. tuberculosis virulence and phagosome maturation arrest, ii) synthesis, function and localization of mycobacterial lipoproteins, iii) improvement of current vaccines, and iv) development of novel drugs.

Task description
Our team uses genetic, biochemical, cell biology and infection biology methods. We are looking for motivated students to become involved in current projects on the above mentioned topics.

Requirements
We are an interdisciplinary, international, young and dynamic group offering a cooperative work environment. We are looking for qualified students who are willing to contribute to the ongoing research projects.

For further details see: Group Sander

Contact
Prof. Dr. Peter Sander
psander@imm.uzh.ch
Tel. +41 44 634 2684