Halting the spread multidrug resistant uropathogenic E. coli (2016–2020)
Urinary tract infections (UTIs) are among the most common infectious diseases of humans and a major cause of morbidity and mortality. UTI is also a major cause of sepsis, which has a mortality rate of 25% and results in more than 36,000 deaths per year in the USA. UPEC are the primary cause of UTI, being responsible for more than 80% of all such infections. In the last decade, we have observed an unprecedented rise in antimicrobial resistance among UPEC and other Gram-negative bacteria. This alarming trend has led to an increased rate of UTI treatment failure with conventional antibiotics and increased dependence on last-line therapies such as carbapenems, further promoting the emergence of multidrug resistant (MDR) UPEC. Recent reports of carbapenem resistance (e.g. via acquisition of the New Delhi metallo-beta-lactamase-1 [NDM-1] resistance gene) among MDR UPEC highlight the gravity of this problem and the looming challenge of treating pan-resistant UTI. In this Fellowship I aim to understand the virulence of MDR UPEC, and use this knowledge to develop new approaches to treat and prevent UTI. Specifically, I will (i) define the molecular mechanisms of MDR UPEC virulence, (ii) determine the molecular function of autotransporter adhesins, (iii) dissect the interactions between UPEC and innate immune cells that influence UTI pathology, and (iv) develop new therapeutic approaches for the treatment and prevention of MDR UTI. The outcomes of my research will be applicable to one of the most common infectious diseases of humans, but also have broad-reaching impact on our understanding of other infections caused by Gram-negative pathogens.