Ins and outs of disarming Type 3 Secretion – understanding resistance to aurodox
Supervisors:
Andrew Roe, School of Infection and Immunity, (University of Glasgow)
Paul Hoskisson, Institute of Pharmacy and Biomedical Sciences, (Strathclyde University)
Rebecca McHugh, School of Infection and Immunity, (University of Glasgow)
Summary:
This project focuses on investigating aurodox, a natural product from Streptomyces goldiniensis, as a potential anti-virulence therapy for Enterohaemorrhagic E. coli (EHEC) infections. EHEC causes foodborne outbreaks of bloody diarrhoea and can lead to Haemolytic Uremic Syndrome, a major cause of acute renal failure in children. Traditional antibiotics are ineffective against EHEC as they can increase Shiga toxin production. Previous work has shown that aurodox downregulates the expression of the Type III Secretion System (T3SS), an essential colonization factor in EHEC and other enteric pathogens. The project aims to understand how aurodox enters bacterial cells and to characterize potential resistance mechanisms. This will be achieved by generating aurodox-resistant mutants in various bacterial strains, identifying resistance mutations through whole genome sequencing, and creating gene knockouts of potentially involved genes. The impact of these mutations on the T3SS will be studied using transcriptional reporter assays, RNA sequencing, and in vivo cell infection models. Additionally, mini-bioreactor technology will be used to evolve aurodox resistance and understand its emergence.