Project Details Fighting microbial resistance through development of new antimicrobial agents, directed against new specific targets

Project No.:
2002-030-1-300
Start Date:
01 January 2003
End Date:
31 December 2007
Division Name:
Organic and Biomolecular Chemistry Division
Division No.:
300

Objective

Increasing resistance of microorganisms against available antimicrobial agents is of major concern amongst scientists and clinicians worldwide. In general, it is observed that pathogenic viruses, bacteria, funghi and protozoa are more and more difficult to treat with the existing drugs. Notorious examples are Tuberculosis, Malaria, AIDS. The objective of the project is to combine international scientific expertise in order to develop new antimicrobial drugs, based on new specific targets.

Description

Resistance of micro+APY-rganisms is the result of normal evolutionary processes of natural selection, that cannot be stopped and in the best cases can be delayed.

Resistance has been observed for (i) viruses, like HIV, the causative agent of AIDS (20% multidrug resistant), (ii) all bacteria, including M. tuberculosis with strains, resistant to 7 of the commonly used tuberculostatics, (iii) funghi, like Candida and (iv) protozoa, with Plasmodium falciparum, causing malaria, as a notorious example of a very resistant pathogen. To effectively combat resistance mechanisms in micro+APY-rganisms, research on new targets should actively continue to develop new weapons in a struggle that will continue forever. In principle, it would be better to design new drugs on a rational basis, than to screen natural sources for new therapeutic agents, since in the latter case it cannot be excluded that resistance already exists in some form in nature, even before clinical trials have started. This research will be directed not only to develop new bactericidal drugs, but also molecules that inhibit virulence, for instance via interference with quorum sensing processes.

Development of new antiprotozoal, antibacterial and antiviral drugs can only be effective if different experts worldwide combine their expertise to tackle the immense problems of humanity in the near future. For this purpose, interactions between (mico)biologists, synthetic and medicinal chemists are essential.

Progress

This project was presented at a poster session at the IUPAC Congress/GA July 2005 >view pdf – 111KB<

The work has been published in various journals. These references include:

Boris Rodenko , Melle Koch,  Lidy van den Burg, Martin J. Wanner and Gerrit-Jan Koomen
The Mechanism of selective Purine Nitration revealed. NMR-studies demonstrate  Formation and Radical Rearrangement of an N-7 nitramine Intermediate
J. Amer. Chem. Soc. 127, 5957 – 5963 (2005)

Tilman Läppchen, Aloysius F. Hartog, Victorine A Pinas, Gerrit-Jan Koomen and Tanneke den Blaauwen
GTP Analogue inhibits Polymerization and GTPase Activity of the Bacterial Cell Division protein FtsZ without affecting its Eukaryotic Homologue Tubulin.
Biochemistry 44, 7879-7884 (2005)

Martin J. Wanner, Melle Koch and Gerrit-Jan Koomen.
Synthesis and Antitumor  Activity  of Methyltriazene Prodrugs Simultaneously Releasing DNA-methylating Agents and the Anti-resistance Drug O6-Benzylguanine.
J. Med. Chem. 47, 6875-6883 (2004)

project completed