Using next generation approaches to define epidemiology and develop therapies for the neglected cystic fibrosis lung pathogen Burkholderia multivorans

Microbial lung infection is the major cause of death in people with CF, with routine therapy often relying on continuous treatment with antibiotics. Several antimicrobial resistant (AMR) pathogens have emerged as problems in CF and transmissible Burkholderia species are one of the main causes of premature death. Epidemic spread of Burkholderia cenocepacia strains caused it to be dominant from the 1990s to early 2000s, but with infection control reducing transmission, Burkholderia multivorans has now become the most common CF Burkholderia. Unlike B. cenocepacia, the pathogenesis and the source of infection for B. multivorans remains elusive. Within the GW4, the supervisory team, EM and AB, represent a unique combination of leading expertise in CF microbiology, and they will work with bioinformaticians (TC), chemists and industry to deliver a cross-disciplinary PhD.

Aim: We will fully define the pathogenesis of B. multivorans, and develop new therapeutics for infection in order to reduce premature death of people with CF. Our hypothesis is "the use of genomics and novel antibiotics isolated from other Burkholderia species will reduce lung infection."

Objectives: 1. Use genomics to define the population biology and virulence of B. multivorans (Year 1). Exeter and Cardiff have excellent genomics facilities, with Cardiff also co-hosting the MRC's Cloud Infrastructure for Microbial Bioinformatics. We have extensive collections of Burkholderia, that will be combined and extended by international collaboration. A systematic panel of global B. multivorans CF and environmental strains will be assembled and genome sequenced. High resolution phylogenomic analysis will be used to fully define B. multivorans population biology, and all sequences shared online to assist global surveillance. Aim 2. Modelling the growth pathogenesis of B. multivorans in vitro and in vivo (Year 2) CF lung infection is characterised by polymicrobial communities (the CF microbiota) growing microaerobically and anaerobically within the clogged mucus. To further understand how B. multivorans grows within sputum, modelling of its low oxygen and anaerobic growth will be performed in vitro. In addition, the virulence of strains from the phylogenomic lineages identified above will be characterised using the Galleria melonella wax moth larvae infection model, in collaboration with Biosystems Technology an Exeter-based spin out. Aim 3. Developing novel therapeutic approaches for Burkholderia infection (Year 3). As part of EM's antibiotic discovery programme, the B. ambifaria antibiotic, enacyloxin IIa, has been found to have a unique activity on B. multivorans and Acinetobacter baumannii strains. The mode of action and potential for resistance of B. multvorans will be investigated using mutant re-sequencing and transcriptomics.