Primary Supervisor: Dr Sandra Beleza, GGB
Secondary supervisor: TBC
PhD project title: Determining the epidemiology and molecular evolution of antimicrobial drug resistance in Cape Verde
University of Registration: University of Leicester
Antimicrobial drug resistance (AMR) is a growing and major public health threat facing the worldwide population of the 21st Century. In addition to the devastating death rates (>700,000 deaths per year globally), enormous financial healthcare costs result from antimicrobial treatment failure, prolonged hospital admissions and the requirement for second-line drug treatment administration. While AMR is widely recognised as being a global challenge, in many countries AMR is still not well understood. For instance, AMR data was not available for 43% of the countries in Africa. To contribute to bridging this gap, this project will focus on the African nation of Cabo Verde and will stem from previous research programme that aimed to characterise the genomic variation, ancestry and evolution of Helicobacter pylori in this country. The potential impact of this research is high since WHO has classified clarithromycin-resistant H. pylori as a high priority pathogen for R&D of new antibiotics. We have previously characterised AMR levels to four antibiotics in a H. pylori sample, whose genomes are available. Known resistance variants are not enough to fully explain the resistance patterns observed. Preliminary Genome-wide Association Studies (GWAS) have identified new candidate variants and genes contributing to observed AMR patterns to Clarithromycin and Metronidazole. Their role in generating resistance needs now to be confirmed and their associated mechanism of resistance accessed. On the other hand, as it commonly happens in GWAS studies, these do not completely account for the AMR patterns observed. The main aim of this project is to use innovative experimental, statistical and evolutionary approaches to characterise the complex genetic architecture, evolution and epidemiology of AMR in H. pylori in Cabo Verde. The specific objectives are:
- To use an experimental evolution approach to characterize the genetics of AMR to the same antibiotics and, in this way, to complement GWAs analyses. We will grow one laboratory strain and two isolates from Cape Verde in sub-lethal antibiotic concentrations. This weak selection pressure has been shown to select for diverse resistance pheno- and genotypes in bacteria. We will we will collect single colonies at extended time points for AMR characterization and whole genome sequencing. We will then characterise genomic variation associated with newly-generated phenotypes and compare it with our population dataset.
- To perform natural transformation experiments using susceptible and resistant strains, to evaluate the roles of mutation and horizontal gene transfer in the development of AMR.
- To integrate results from 1. and 2. with previous and new GWAS analyses, inclusively using a bigger cohort of strains characterized for Metronidazole and Clarithromycin resistance.
- To evaluate the genetic diversity and evolution of AMR in pylori in Cabo Verde. To characterize the genetic variation and to perform population genetics and phylogenetic analyses with both susceptible and resistant strains to evaluate the role of the population genetic structure and of the action of the antibiotic selective pressure in the evolution of AMR in H. pylori strains in the country.
This project will provide a more complete understanding of AMR in H. pylori and potentially will provide new drug targets. Information about the rate, origin and evolution of AMR in Cabo Verde will inform national public-health policies and our research that has implications for other African Low- and Middle-Income Countries which have similar health care systems.
BBSRC Strategic Research Priority: Understanding the Rules of Life, Microbiology
Techniques that will be undertaken during the project:
The project involves mostly computational, evolutionary (phylogenetics and population genetics), experimental (bacterial growth and passage, transformation analyses, tests for antimicrobial drug susceptibility) and statistical analyses. It will also include molecular genetics (e.g. DNA extraction, DNA library construction, PCR, RT-PCR), and NGS using paired-end sequencing.
Contact: Dr Sandra BelezaLink opens in a new window, University of Leicester