Our objective is to define inhibitable targets in proteins required for bacterial proliferation. The molecular structure of these targets will be used by the industrial partners to design lead compounds to develop new chemotherapeutics, which are needed to overcome the rapidly increasing resistance of pathogenic microorganisms to classical antibiotics. The ability to effectively treat microbial infections will reduce morbidity, improve recovery from modern surgical techniques and generally positively impact on health management policies.
Recently found protein-protein interactions between different components of the bacterial septation machinery offer new opportunities to design these novel antimicrobials. Targets will be sought in the proteins involved in the formation of the bacterial septum and in the assembly of the cell wall. Identification of the targets will be achieved by studying protein-protein interactions, defining the interacting domains and testing their ability to be inhibited by peptides and small compounds of known structure. Many of the proteins which form part of the septation machinery are encoded by genes which are conserved in disparate microorganisms.
This phylogenetical conservation will be used to an advantage to design inhibitory compounds effective for a wide spectrum of microorganisms. This project aims at fulfilling the objectives stated in the Cell Factory Workprogramme which specifically read: "development of molecular inhibitors capable of bypassing microbial resistance to antibiotics" (area 1.1.1, page 29 of the Workprogramme). We will develop inhibitory compounds which will reasonably yield one novel candidate drug for entry into development phase no later than 2 years after the completion of this project.
Achievement of the objectives demands a multi- disciplinary strategy, from classical optical microscopy, to the most innovative molecular design, with Molecular Genetics supplying their interconnection. The partnership includes 9 laboratories from 6 different countries which are world- leading experts in Molecular Genetics, Structural Analysis, IR-ATR Spectroscopy, Peptide Screening and Microscopy.
Exploitation of the results is guaranteed by the participation as full partners of two leading pharmaceutical companies. A strategic aim of these industrial partners - Glaxo Wellcome and Smith Kline Beecham (SB) - is the definition of new targets in clinically relevant microorganisms using current and future knowledge derived from studies on cell division.
Funding SchemeCSC - Cost-sharing contracts
72076 Tübingen 1
CM19 5AD Harlow
OX1 3RE Oxford
1098 SM Amsterdam
EH9 3Jr Edinburgh