Abstract
The evolution of antimicrobial resistance, and its subsequent emergence, have been identified as one of the great challenges of a generation. This evolutionary process has the capacity to render available therapies and control strategies ineffective. In turn, treatment failure can allow a relevant microbial pathogen to increase in prevalence and enable onward transmission. The significance of this for medicine, economic productivity, as well as ecological balance, maintenance of natural ecosystems and native taonga, should not be understated. This thesis details three original research projects, aimed at addressing the emergence of resistance.
First, to support the appropriate use of antibiotics, novel methods of identifying genetic signatures of resistance are established here, with a focus on application of these diagnostic methods at the point-of-care. Based on enzyme-assisted profiling of DNA sequences, these methods increase the resolving power of current gold standard methods, and allow accurate prediction of resistance at sites that were previously beyond the scope of these approaches. The translational nature, and commercial potential, of this work led it to be awarded the Division of Health Sciences ‘Translational Research Grant’ (2015), and the Otago Innovation ‘Proof of Concept Award’ (2016), with the generated intellectual property being the basis of a patent application (2017).
Secondly, the use of next-generation sequencing to identify signatures of resistance was explored. Advances in this field continue to revolutionise our scientific understanding of resistance, as well as expanding the repertoire of tools available to survey and control its emergence. An exploratory and systematic search of public next-generation sequence databases showed synthetic nucleic acid sequences are a frequent contaminant in next- generation sequence data. These sequences can harbor antibiotic resistance genes, appearing at rates sufficient to impact both the study of antibiotic resistance and confound prediction of antibiotic efficacy in clinical settings. These findings have been presented internationally, with measures introduced to public sequence databases to address the observed contaminant sequences.
Agricultural applications of antimicrobials are a major driver of resistance globally, with established flow-on effects in both agricultural and clinical settings. In New Zealand, agricultural use of antibiotics is limited compared to other nations, although assessment of resistance in this setting has value.An exploration of the phylogenetic history and evolutionary trajectories of globally-sourced Streptococcus uberis, a major agricultural pathogen in New Zealand cattle, was made here. This revealed geographically defined lineages, varying rates of antimicrobial resistance, and presents a hypothesis for a novel genetic basis of the observed high-virulence and subclinical phenotypes observed in the species.
A series of short perspective essays, elaborating on the themes and ideas relevant to the presented works, are provided. Each aim to place the collected research in a broader social and scientific context.