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The unknown cellular gates: managing traffic through bacterial membrane transporters

To date, approximately one-third of the world’s population is harboring Mycobacterium tuberculosis (M. tuberculosis, Mtb), the causative pathogen of Tuberculosis (TB), a disease recognized by the World Health Organization as a world health threat.

Prolonged treatment regimes and newly arising drug resistance demands the development of new drugs.(Cegielski, 2010) Over the past years, most of the approved anti-mycobacterial drugs have been identified in cellular screens, where potent drugs have been mainly identified accidentally by screening huge compound libraries to find a single lead structure. The low hit rate is, among other things, attributed to the thick and waxy mycobacterial cell wall, which hinders small molecules from entering cells and thereby holds them from reaching their intracellular target.(Jarher & Nikaido, 1994)

Recent research efforts point towards the fact that transporter mediated uptake of small molecules is much more prominent than initially thought and, on the other hand, passive diffusion through the cell wall hardly occurs.(Sarathy, Dartois et al., 2013) Concentrating our research on the discovery of carrier systems in Mycobacterium tuberculosis, the causative agent of tuberculosis, can revolutionize the field. Starting from already approved drugs we will be able to identify suitable solute transporters for drug uptake. Piggybacking of drugs on an active transporter system into the mycobacterial cell offers great potential in tuberculosis drug discovery and holds great promise in increasing drug selectivity and potency.

The concept behind our research is the development of chemical probes to study the biology of mycobacterial membrane transporters, especially in the context of drug uptake. We think that carrier systems can be specifically engaged to channel drug uptake in cells and we are interested in employing this concept in the design of new anti-mycobacterial agents. Along these lines we would like to study the underlying mechanisms of membrane transporter selectivity and function and develop new methods to analyze these fascinating proteins and their natural cargo by means of mass spectrometry.

We use a multidisciplinary approach in order to find new ideas and solutions for the treatment of mycobacterial infections, such as tuberculosis.

Currently, we are interested in the following topics:

  • Chemical trojan horses for targeted drug delivery (A)
  • Pull-down strategies to identify drug transport systems (B)

 

 

References

[1] Cegielski JP (2010) Extensively drug-resistant tuberculosis: "there must be some kind of way out of here". Clin Infect Dis 50 Suppl 3: S195-200
[2] Jarher V, Nikaido H (1994) Mycobacterial cell wall: Structure and role in natural resistance to antibiotics. FEMS Microbiol Lett 123: 11
[3] Sarathy J, Dartois V, Dick T, Gengenbacher M (2013) Reduced drug uptake in phenotypically resistant nutrient-starved nonreplicating Mycobacterium tuberculosis. Antimicrob Agents Chemother 57: 1648-53

 

Contact

Dr. Claudia Jessen-Trefzer

Institute of Pharmaceutical Sciences
Stefan-Meier-Str. 19
79104 Freiburg

Phone: +49 (761) 203 8381
Fax: +49 (761) 203 8383