Inhibitors Of Bacterial Protein Synthesis - A New Class Of Antibiotics
Funder
National Health and Medical Research Council
Funding Amount
$120,000.00
Summary
Pioneering work by CSIRO scientists has identified specific peptide motifs in the DNA replication machinery of bacteria that are critical for the correct functioning of the organism. In collaboration with CI Alewood potent (Kd ~ nM) lead compounds that inhibit bacterial DNA replication have been designed and synthesised. Through the application of a number of novel bioinformatics approaches to the analysis of the complete genome sequences of bacteria, the key sites of interaction of a number of ....Pioneering work by CSIRO scientists has identified specific peptide motifs in the DNA replication machinery of bacteria that are critical for the correct functioning of the organism. In collaboration with CI Alewood potent (Kd ~ nM) lead compounds that inhibit bacterial DNA replication have been designed and synthesised. Through the application of a number of novel bioinformatics approaches to the analysis of the complete genome sequences of bacteria, the key sites of interaction of a number of protein families (DNA synthesis and repair enzymes) with the beta subunit of bacterial DNA Polymerase III have been identified. The nature of the sites, and preliminary experimental data, suggests that the approach will be generally applicable to all species of bacteria. In addition a wide range of novel assays for the identification of inhibitors of the interaction of proteins with the beta subunit have been developed. In this proposal we wish to demonstrate that our in vitro nanomolar inhibitors of the beta subunit can inhibit bacterial cell growth. The development program proposes to develop methods and strategies to gain bacterial cell entry of inhibitors of the interaction of proteins with the beta subunit of bacterial DNA Polymerase III. Proof of concept will be demonstrated by inhibition of bacterial cell growth. Stable compounds with good binding characteristics and able to be taken up by cells will be developed based on structure-function assay results, structural studies and modelling of inhibitors bound to the target. Antimicrobial activity of compounds will be demonstrated in standard FDA approved NCLLS (National Centre of Clinical Laboratory Standards USA) tests. Spectrum of activity will be demonstrated by testing compounds against bacterial species representative of the range of pathogenic organisms in standard FDA assays.Read moreRead less
The proposed project is part of a research programme aimed at developing a new drug to reduce the side effects of cancer radiotherapy. These side effects result from the radiation damage to normal tissues close to the tumour. Since in many instances the normal tissues at risk are accessible to topical application (eg. skin in breast cancer patients, rectal mucosa in prostate cancer patients, oral mucosa in all patients being treated for tumours in the head and neck region) the concept is very si ....The proposed project is part of a research programme aimed at developing a new drug to reduce the side effects of cancer radiotherapy. These side effects result from the radiation damage to normal tissues close to the tumour. Since in many instances the normal tissues at risk are accessible to topical application (eg. skin in breast cancer patients, rectal mucosa in prostate cancer patients, oral mucosa in all patients being treated for tumours in the head and neck region) the concept is very simple. A drug which makes cells less sensitive to X-rays (these drugs are called radioprotectors) is simply applied topically to the normal tissues at risk. For this purpose, we have developed a new radioprotecting drug called methylproamine which is 100-fold more potent than previously-developed radioprotectors. Unfortunately, methylproamine is not suitable for our purpose because at higher concentrations it is toxic to some cells. This hurdle must be overcome in order to make the project attractive to potential commercial sponsors. Our aim is to modify methylproamine by removing the molecular features that cause the cytotoxicity. We have established that this is feasible, by synthesising and evaluating a small family of methylproamine analogues. Some less toxic family members have already been identified. With this knowledge, we now propose to use special computer programmes to design a much larger family of methylproamine analogues, and to synthesise and test each one in order to identify the most promising candidate for our purpose. Once the efficacy window hurdle is passed, the subsequent milestones to commercialisation and clinical implementation can be addressed, with appropriate sponsorship. An Australian company has already expressed strong interest and is evaluating the opportunity.Read moreRead less