The emergence and impact of azithromycin-resistant Salmonella enterica serovar Typhi

Typhoid fever is a life-threatening infectious disease that requires antibiotic treatment to avoid deaths and complications. However, the global spread of extensively drug-resistant (XDR) S. Typhi threatens antibiotic therapy, leaving azithromycin the only remaining oral drug effective against XDR typhoid. Concerningly, azithromycin resistance has recently appeared in South Asia, posing an imminent threat of untreatable typhoid. Here, I will decode the genetics of S. Typhi samples from South Asia to investigate the epidemiological and evolutionary pathways of azithromycin-resistant S. Typhi. I will also perform experiments to identify factors driving the emergence of azithromycin-resistant S. Typhi and determine the effects of resistance-conferring mutations on the organisms' survival and fitness. Further, I will investigate the correlation between azithromycin treatment responses and azithromycin susceptibility of S. Typhi organisms inside and outside of the human cells. This project will generate important data to guide public health control measures and improve treatment of typhoid fever.