Understanding how Gram-positive pathogens sense and respond to daptomycin (360G-Wellcome-203812_Z_16_A)

Antibiotic resistance is a growing threat to human health as it results in infections which are difficult to treat and are associated with high rates of mortality. Daptomycin is a last-resort antibiotic used to treat infections caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. However, daptomycin fails to cure approximately 20 % of infections. Bacteria can protect themselves from daptomycin by releasing lipids from their cell membranes which prevent the antibiotic from reaching and killing its target. Understanding more about this bacterial defence mechanism is important as it will allow development of novel approaches to improve the effectiveness of daptomycin therapy. Therefore, the aim of this project is to understand how S. aureus senses the presence of daptomycin and how this leads to the production of lipids. I will determine which proteins are necessary for this defence mechanism and whether other Gram-positive pathogens also sense daptomycin and induce the release of lipids in a similar way to S. aureus. These studies will lead to a greater understanding of this novel resistance mechanism and may lead to the identification of factors which could be targeted therapeutically to reduce the pathogen’s defences and therefore improve rates of daptomycin treatment success.