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Antimicrobial penetration into real skin biofilms


   School of Life Sciences

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  Dr K Hardie, Dr L Martinez-Pomares  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Biofilm formation is key to the progression of infections. Biofilm is a particular problem for people susceptible to chronic infections (e.g. those with burn wounds, diabetic ulcers) and biofilms are recalcitrant to antimicrobial therapies. We need novel antimicrobial strategies to overcome these challenging clinical scenarios. Our current understanding of in vivo biofilms is limited. The complexity of these environments, that comprise several species of bacteria in close proximity with host cells, is challenging to study. Both the biodiversity and the spatial structure of in vivo biofilms are hard to mimic using in vitro models. We have developed in vivo-like polymicrobial biofilm platforms for chronic skin wounds. The models include the reductionist skin cell monolayers, and more realistic (but more complex) 3D ex-vivo models that are created from excess porcine ears derived from the food industry and post-surgery human skin that would otherwise be discarded.

This studentship will use our infection models to identify the barriers to antimicrobial penetration and treatment of biofilms, with the aim of developing novel strategies to overcome them. To do this, the student will use state-of-the-art OrbiSIMS: this is the only way to look at the interactions of extracellular molecules with the biofilm matrix and bacterial cells in 3D. Combining OrbiSIMS with microbiological and immunological techniques will enable the student to (i) visualise the distribution of topically-applied antimicrobials within a realistic biofilm; (ii) determine the proportion and distribution of antimicrobial susceptible bacteria present in the biofilm, (iii) characterize the metabolic responses to the antimicrobials of the bacteria (do they die or become dormant?) and host cells (is wound healing impeded?), (iv) map the spatiotemporal distribution of bacterial signalling/virulence factors in biofilms, and (v) detect any immunological response from host tissue. This work will underpin the identification of novel antimicrobial strategies, or biomarkers that could be used as the basis of diagnosis.

The supervisors are co-Investigators of the National Biofilm Innovation Centre (NBIC), and have vibrant research groups hosted in state of the art laboratories of the Biodiscovery Institute and Medical School on the main University of Nottingham Campus. Kim Hardie has an extensive track record in molecular microbiology of pathogenicity and Luisa Martinez-Pomares in Immunology.

The training opportunities include fluorescent microscopy, Cytokine analysis, cryo-OrbiSIMS, tissue culture, and molecular microbiology microbiology. In addition the University offers a host of practical training courses, there is an active research seminar programme and wellbeing support.

References

Singh, N., Romero, M., Travanut, A., Monteiro, P., Jordana-Lluch, E., Hardie, K.R., Williams, P., Alexander M., and Cameron Alexander, C. (2019) Dual bioresponsive antibiotic and Quorum Sensing inhibitor combination nanoparticles for treatment of Pseudomonas

Brown, J.M., Williams, P., and Hardie, K.R. (2019) Microfluidic-based growth and imaging of bacterial biofilms. In Press Bio-101. https://bio-protocol.org/bio101/about.aspx. https://en.bio-protocol.org/bio101/e3460

Barzan, G., A. Sacco, A., Mandrile, L., Giovannozzi, A.M., Brown, J., Portesi, C., Alexander, M., Williams, P., Hardie, K.R., and Rossi, A.M. (2020) New frontiers against multi-drug resistance: A Raman-based approach for detection of bacterial viability and cross-induced antibiotic resistances within 1 hour. Sensors and Actuators B: Chemical. https://doi.org/10.1016/j.snb.2020.127774

Jordana-Lluch, E., Garcia, V., Kingdon, A., Singh, N., Alexander, C., Williams, P., and Hardie, K.R. (2020). Development of a polymicrobial model to examine interactions between commensals and pathogens on skin. Frontiers in Microbiology 11:291. doi: 10.3389/fmicb.2020.00291.

Zhang, J., Brown, J., Scurr, D., Bullen, A., McLellan-Gibson, K., Williams, P., Alexander, M.R., Hardie, K.R., Gilmore, I.S., and P. D. Rakowska, P.D. (2020) Label-free 3D molecular imaging of a P. aeruginosa biofilm using cryo-OrbiSIMS. Analytical Chemistry https://doi.org/10.1021/acs.analchem.0c01125. https://www.biorxiv.org/content/10.1101/859967v1