Assessment of the activity of novel antimicrobial therapies against bacterial biofilms: establishing a resource to support non-microbiologists 

Overview

Bacteria often exist in communities called biofilms. When these biofilms form on the surface of in-dwelling medical devices, it becomes a serious clinical problem because the infections seem recalcitrant to antimicrobial treatment and therapies.  Thus therapeutic approaches targeting these communities and their formation might improve the efficacy of currently available antibiotics.

This project brought together microbiology expertise (Van der Woude, CII) to test effectiveness of novel antimicrobial therapies under development, specifically: modifying drugs to circumvent resistance (Duhme-Klair and Routledge, Chemistry), identifying bacterial targets for biofilm inhibiting agents (Potts, Biology), and biomedical plasmas (Vann,Plasma Institute). An additional aim was to support the establishment of a University “biofilm interest” network through which resources and strategies can be shared, and to encourage the development of complementary strategies.

In detail

Biofilm growth of bacteria, a mode of growth particularly associated with chronic infections, can confer drug resistant behaviour, complicating treatment of infections. This project brought together microbiology expertise (Van der Woude, CII) to test effectiveness of novel antimicrobial therapies under development, specifically: modifying drugs to circumvent resistance (Duhme-Klair and Routledge, Chemistry), identifying bacterial targets for biofilm inhibiting agents (Potts, Biology), and biomedical plasmas (Vann,Plasma Institute). An additional aim was to support the establishment of a University “biofilm interest” network through which resources and strategies can be shared, and to encourage the development of complementary strategies.

Work that was carried out between the Van der Woude and Duhme-Klair and Routledge groups introduced expertise in Pseudomonas aeruginosa (P.a.), a major pathogen especially in cystic fibrosis microbiology, into the Centre for Immunology and Infection (CII). The work identified a suitable assay from the literature, and developed and applied this to P.a. for determining biofilm penetration of novel 'Trojan' horse antimicrobials. Results showed that chemical modifications have unpredicted effects on biofilm penetration. This will inform future compound design. Data are included in a joint manuscript on these novel compounds that is in preparation (to be submitted before end of 2013). The assay, which is now well-established, can be applied to new compounds in the future.

The Potts group study the formation of staphylococcal biofilms from a structural biology perspective. It is essential that hypotheses based on the protein structures can be tested in-house in biofilm assays and the funding has now provided this capability. Fundamental differences in aggregation behaviour were observed between strains reported previously to form protein- and carbohydrate-mediated biofilms. Other data support and extend observations regarding the two types of biofilms. An understanding of the relationship between the two mechanisms is key to further studies on developing therapeutic strategies for Staphylococcal infections. The work supported and extended a project funded by the British Heart Foundation. Two manuscripts related to staphylococcal biofilm formation are currently in preparation.

Adaptations to the plasma equipment setup in the CII made applications to biological samples much more amenable. The setup allows the parameters (V, distance, etc) to be adjusted so that biologically important parameters (temperature for example) can be measured and controlled. Investigations building on initial data helped develop ideas that became part of a funded N8 Universities Research Partnership project on the biological activity of plasma. Furthermore, a WT funded PhD student (CIDCATS programme) has been attracted to this project, further strengthening the interactions with the Plasma Institute staff. Findings and experiences are shared with the Plasma Institute and inform its work on cancer led by Norman Maitland. The equipment, protocols and acquired expertise is continuing to support ongoing work. Finally the accessible setup in the CII has already facilitated interactions with other biologists to assess novel applications of plasma to biological questions. For example in the field of neuroscience Sean Sweeney of the Department of Biology has been exploring using plasma as a means to apply reactive oxygen stress.

The key goal of sharing knowledge and insights centred on bacterial infections has been achieved. Benefiting from regular discussions, all parties have gained appreciation of the potential and complexities of each other’s fields of expertise.

Outputs

Grants

• Anne-Kathrin Duhme-Klair, EPSRC, Siderophores as anchors in artificial metalloenzymes, £627,905
• Deborah O'Connell, N8 Industry Innovation Forum, Novel plasma-activated technologies for biofilm control, £35,000
• Jennifer Potts, British Heart Foundation, Senior Basic Science Fellowship Renewal J Potts, £664,192