Periodic Reporting for period 1 - COMMANDEER (COMMANDEER: Disrupting microbial resistance using rationally designed signalling molecules)
Reporting period: 2015-07-01 to 2017-06-30
Traditionally, antibiotics have been used to combat bacterial infections. Although these compounds were initially highly effective, they resulted in substantial stress on the target bacterium, which rapidly selected for multi-antibiotic resistant bacteria. Additionally, the number of new effective antibiotics brought to market is steadily falling.
The overall aim of COMMANDEER was to build upon a very promising pilot study demonstrating that DSF analogue compounds interfere with cell-to-cell signalling processes in P. aeruginosa making them significantly more susceptible to antibiotic treatment. We have identified antagonists which can be co-administered with current antibiotics forming the basis of future therapies for CF. We carried out a deeper investigation of the relationship between structure and activity, ability to permeate biofilms and spectrum of activity of these analogues. A collaborative and multidisciplinary approach was used, incorporating chemical and biomolecular techniques, to generate a library of bioisosteric analogues of DSF, evaluate their ability to interfere with DSF cell-to-cell signalling processes in bacteria that colonize the CF lung and select those compounds which improve the efficacy of antibiotic treatment of bacterial infections.
It has previously been found that antibiotics which readily permeate biofilms are the most effective against biofilm-producing bacteria. During the course of this project, a study was undertaken to develop a model system using high performance liquid chromatography (HPLC) retention times as an method of determining lipophilicity. This data is being mapped to biological activity thereby ascertaining the correlation between efficacy and lipophilicity.
Knowing that DSF and BDSF quorum sensing is shared across many different microbial species, we sought to maximise the chances of success of our compound library by seeking out researchers who could use these molecules as potential investigative tools. While in depth biological testing is still on-going, we have already received very promising results. In the case of P. aeruginosa, we have identified that a number of our compounds are indeed active and inhibit biofilm formation at micromolar concentrations. Interestingly, when the same library was tested by our collaborators in Spain, they also found that the same compounds inhibited biofilm formation in S. maltophilia again at micromolar concentrations. This is an especially exciting result as it demonstrates that our compounds have potential application across several microbial species as general agents for disrupting biofilm formation and antibiotic resistance.
This project also included an industry secondment. During this time, we worked to further optimise the synthetic route to these compounds, with a particular emphasis on scale-up of the current route. The co-administration of our active compounds with current antibiotics was investigated. Results from these studies are promising as they indicate that the Minimum Inhibitory Concentration (MIC) of a current antibiotic was reduced 6 fold when one of compounds was co-administered with that same antibiotic. This, again, is an exciting result, as it demonstrates that our compounds do indeed improve the efficacy of existing antibiotics, one of the central aims of this project.
More specifically, in the case of CF patients, it has been observed these patients are invariably co-infected with multiple bacterial species. These infections typically include both P. aeruginosa and S. maltophilia – the two species which have proven sensitive to our compounds thus far. Therefore, our compounds are likely to be especially beneficial to CF patients who have acquired polymicrobial infections. This will lead to improved quality of life for patients with a disease which is especially prevalent in Europe.
A major impetus for this project is growing problem of bacterial resistance and reduced effectiveness of current antibiotics. By co-administering our molecules with existing antibiotics, we could significantly improve their efficacy and give these antibiotics a greatly extended “shelf life”. This would mean that drugs that were otherwise consigned to the dustbin due to bacterial resistance can again be effective therapies. Gratifyingly, over the course of this project, we have proven that co-administration of our compounds with an existing antibiotic results in a 6 fold reduction in the Minimum Inhibitory Concentration (MIC).
This project has boosted University College Cork’s existing research profile in bioactive molecules and has enabled us to expand into the development of novel anti-microbial agents. These compounds can be licensed to the European pharmaceutical sector in future. We have established new collaborations with biologists in Europe and beyond and we will maximise the impact of this fellowship by sharing our compounds with several collaborators. This project has increased European research output with the publication of high impact publications in peer-reviewed journals, presentations at national and international conferences, and attracting external funding to continue this research.