Characterising the role of bacterial multi-drug efflux pumps in virulence

Salmonella are listed as high priority for the development of new treatments by the WHO due to increasing antimicrobial resistance (AMR). Multidrug efflux pumps, like AcrAB-TolC, are fundamental in AMR because they confer resistance to virtually all antibiotics. Beyond AMR, efflux pumps are pivotal to the virulence of bacterial pathogens that inflict devastating disease burden on humans, animals, and plants. Yet, the mechanism by which efflux pumps impact virulence is not understood. In this project, I will unravel the fundamental role of efflux pumps in infection using Salmonella enterica serovar Typhimurium (S. Tm), a model pathogen where efflux pump function is essential for virulence. Using molecular biology, metabolomics, and transcriptomics, I will identify virulence-associated metabolites exported by efflux pumps, dissect how efflux activity affects host-pathogen interactions, and unveil regulatory networks connecting efflux pump activity with the expression of key virulence genes. This research will shed light on why efflux pumps are indispensable for bacterial virulence and lay the foundation for novel anti-virulence therapeutics. Given the essential role of efflux pumps across a broad spectrum of significant bacterial pathogens, this work will have far-reaching implications beyond the Salmonella field and catalyse future research into strategies to combat bacterial virulence.