Stage M2S3 (2019-2020)

Aminoglycosides are antibiotics indicated for the treatment of serious infections (e.g., septicemia, meningitis, peritonitis). These drugs are active against a broad spectrum of bacteria, mainly gram-negative aerobes. Activity is dose-dependent and does not require prolonged administration. Streptomycin, a natural product of a bacteria of the Streptomyces genus, is the first-in-class. It is indicated for the treatment of tuberculosis. Aminoglycosides are mainly administered by injection, as the drug is not absorbed by the intestine.

Aminoglycosides bind to 30S ribosomal subunit of susceptible organisms and consequently inhibit the protein synthesis. However, they may also target mitochondrial ribosomes in some epithelial or sensorial cells, possibly causing hearing loss, gaze instability and balance impairments. Aminoglycosides may also cause kidney damage. Adverse effects are frequent, can happen at low dose and some are permanent.

Since aminoglycosides have been massively used during the last 60 years, resistant bacterial strains have emerged. The drug is turned into an inactive substance by specific metabolic enzymes. Three main classes of aminoglycoside metabolic enzymes have been characterized: phosphotransferases, nucleotidyltransferases, acetyltransferases.

Chemical modifications of natural aminoglycosides have been proposed to address the efficacy, toxicity and resistance issues. This strategy was successfully used in the development of amikacin from the natural product kanamycin (from Streptomyces kanamyceticus).

In a collaborative project involving chemists (JM Weibel, umr7177), biologists and physicians (G Prévost, EA7290), biophysicists (E Ennifar, upr9002) and modelers (E Kellenberger, umr7200), we have aimed at developing safe and effective derivatives of natural product neomycin (from Streptomyces fradiae). Preliminary data have already revealed key modifications to increase antibacterial activity against resistant strains while reducing toxicity.

The subject of the internship is part of the process of rationalizing the design of neomycin derivatives. The project aims at collecting all available 3D-structures of aminoglycoside metabolic enzymes. It involves the following tasks: the survey of the literature, the search of the Protein Databank, the visual analysis of 3D structures and the reporting of data.

This project may be continued in the second semester, as part of the research internship, with the modeling of the recognition of aminoglycoside metabolic enzymes by neomycin synthetic derivatives.

We are seeking a motivated student, with a well-structured and well-organized way of working.





Contact: Prof Esther Kellenberger, Faculty of Pharmacy This email address is being protected from spambots. You need JavaScript enabled to view it.



Selection of recent reviews:
(1) Thamban Chandrika, N.; Garneau-Tsodikova, S. Comprehensive Review of Chemical Strategies for the Preparation of New Aminoglycosides and Their Biological Activities. Chemical Society Reviews 2018, 47 (4), 1189–1249. https://doi.org/10.1039/C7CS00407A.
(2) Bera, S.; Mondal, D.; Palit, S.; Schweizer, F. Structural Modifications of the Neomycin Class of Aminoglycosides. MedChemComm 2016, 7 (8), 1499–1534. https://doi.org/10.1039/C6MD00079G.
(3) Fosso, M. Y.; Li, Y.; Garneau-Tsodikova, S. New Trends in the Use of Aminoglycosides. Med. Chem. Commun. 2014, 5 (8), 1075–1091. https://doi.org/10.1039/C4MD00163J.