Dendron-based synthetic bacteriophages for the treatment of proteus mirabilis infections

Abstract

In the last two decades a surge in antibiotic resistance has limited antibiotic effectiveness increasing the risk of uncontrolled epidemics especially for biofilm-related infections. The National Institute of Health reports that 80 % of human infections are biofilm related. The Proteus mirabilis bacteria were focused on in this study as they are significant biofilm formers in chronic infections such as biofilm-related urinary tract infections for which there are currently no completely effective treatment strategies. As biofilms can increase antibiotic resistance by up to 1000-fold, there is an urgent need for the development of novel antimicrobials. Thus, bacteriophages which are viruses that target and kill bacteria have been proposed as suitable alternatives, but factors like storage stability and re-isolation pose limitations. Towards investigating the development of new antimicrobial strategies, the aims of this thesis were to assess: (i) the therapeutic potential of bacteriophages against Proteus mirabilis biofilms and (ii) the development of a novel antimicrobial strategy based on a synthetic biology approach for improvement of bacteriophage-based biofilm control. The work presented in this thesis led to or may lead to four areas of development, which have the potential to contribute to fields of biofilm research, bioengineering and materials science. Firstly, novel bacteriophages against clinical strains of Proteus mirabilis were isolated with physicochemical and genomic characterisation. Unlike other studies, the effect of temperature was included in the selection of favourable bacteriophages for anti-biofilm use. Secondly, towards improving bacteriophage-based treatment, dendrimeric nanoparticles known as dendron were posed as alternatives, these were synthesised and characterised, and demonstrated improved biofilm reduction and eradication by 35 % and 100 % respectively compared with the most effective bacteriophage.Thirdly, this study developed insight into the dendron’s mechanism of action, which was previously unreported, and was proposed to be through disruption of Proteus mirabilis DNA systems. Fourthly, in a unique approach, the dendron was bioengineered with bacteriophage DNA using electrostatic interactions. The results suggested that the dendron has potential to be used as a carrier for bacteriophage DNA, and presents the first attempt in published literature at combining the anti-biofilm properties of bacteriophages and dendrons towards futuristic development of synthetic bacteriophages. The results also provide a promising antimicrobial strategy for use of dendrons as therapeutic agents, alone or in combination with antibiotics and bacteriophages for treatment of biofilm-related infections.

Date of Award	2016
Original language	English
Awarding Institution	University of Brighton