Dissecting the bacterial genetics of bloodstream infection

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Escherichia coli is the bacterial pathogen most often associated with bloodstream infection. This is a major health concern considering that a patient acquiring such an infection can develop sepsis, the body's potentially lethal chain reaction to infection of the bloodstream. Sepsis affects around 50 million people worldwide every year, with a frightening one in five chance of death. Furthermore, bloodstream infections were responsible for one third of the 1.27 million deaths directly caused by antimicrobial resistance in 2019. The World Health Organization ranks E. coli as a critical priority for discovery of new treatment strategies, due to it being the leading organism responsible for deaths arising from drug resistance. There are currently around 40 new antibiotics in development. However, many of these are not active against Gram-negative bacteria such as E. coli and it is inevitable that they will not all win approval for clinical use. It is therefore clear that these potential drugs will not meet the increasing demand in society and, without the discovery of new treatment approaches, annual deaths from antimicrobial resistant infections are estimated to rise to 10 million by 2050. One strategy to combat this problem is to design targeted treatments against pathogens. However, in order to identify what these targets are, we must first gain a deep, fundamental understanding of how bacteria cause infection. Bacterial genes act as blueprints describing the molecular machinery that they use to live. However, pathogens can alter which genes they require in unique ways, making their blueprints difficult to understand depending on the type of infection. We currently lack an understanding of how E. coli uses its molecular machinery to infect the bloodstream and spread throughout the body. I will address this gap by discovering the specific genes and associated molecular processes that are required for E. coli to cause potentially lethal bloodstream infections. By understanding the molecular requirements of pathogens to function within the host, we can exploit this knowledge to develop vaccines or inhibitors that specifically block these processes. This research will reveal the underlying processes of bloodstream infection and therefore has the potential to reveal urgently needed targets for future drug development.