Identification of novel double-stranded RNA elements in developing antibiotic resistance in the agricultural environment
Dr. Daniel Rigden, University of Liverpool
Moreton Morrell College, Warwickshire
Dr. Igor Morozov, Dr. Jess Rollason and Dr. Lauren Acton, Coventry University
The goal of the project is to identify and subsequently characterise the dsRNA dimension of the animal gut microflora (both the differential presence of antisense bound to mRNA and phage dsRNAs containing novel genetic information in response to AB pressure). Identification of novel functional dsRNAs (asRNA bound to its target and phage dsRNAs involved in AR) will mark a paradigm shift in our understanding of the development of AR and future approaches to treating infections.
This work will lead to a fundamental shift in our view on the development, transmission and regulation of AR and bacterial pathogenicity in agricultural settings. This project will result in identification of new targets for novel and possibly existing antibacterials, thus paving the way for industry to re-stimulate research in antibiotic drug discovery. Results from this proposal will inform the UK government and other policymakers (via One Health framework) on the use of clinically relevant drugs in agricultural settings, such as farms in order to prevent potential appearance of clinically relevant AR determinants on mobile elements which are controlled by anti-sense RNAs.
Exploitation of our work has significant potential for Pharmaceutical industries in developing novel strategies and designing new generation therapies based on novel targets. Results will be shared via Antibiotic Action initiative groups across the globe.
The results of this proposal in the long term will be important for development of new combination therapies, as this research has a great potential to identify new regulatory elements (coding and non-coding), AR determinants associated with bacterial communication and mechanisms which can be regulated in response to antibiotic pressure (e.g. switching on adaptive mechanisms, including the excludon). This could lead to follow up studies to this project by screening new therapies based on the use of novel agents (asRNAs or novel RNA-based drugs) to silence mechanisms responsible for transmission of AR in conjunction with known antibacterial to treat the infection. Mutations in the targets (as a mechanism of developing AR) of asRNAs are unlikely to influence the efficiency of asRNA-mRNA binding and, therefore therapy. asRNAs are from tens to hundreds of nucleotides, so are generally long enough to maintain a strong interaction despite mutations in mRNA targets. Resulting new antibacterials with a reduced capacity for resistance long term would significantly benefit the NHS and the cost of care, increase efficiency of health care, life expectancy and reduce the risk of invasive surgery and treatments. This will result in saving millions of lives world-wide and save the National Health Service millions of pounds.