Canagliflozin reduces the recovery of intracellular uropathogenic Escherichia coli from uroepithelial cells and affects α-hemolysin function

Abstract SGLT2 inhibitors, used for diabetes treatment, have been discussed with an increased urinary tract infection (UTI) risk due to increased glucose excretion in urine. Beyond their primary function, these drugs exhibit diverse off-target effects. We investigated whether canagliflozin and other SGLT2 inhibitors impact the interaction between the host and uropathogenic Escherichia coli (UPEC), as well as UPEC pathogenicity. In vitro cultures of uroepithelial cell lines were infected with UPEC strains CI5 and CFT073. Effects of different SGLT2 inhibitors were assessed by measuring the intracellular bacterial burden, glucose uptake and ATP levels of host cells, and the hemolytic activity of the toxin α-hemolysin. Canagliflozin showed the most pronounced and consistent reduction in intracellular UPEC recovery, while ipragliflozin showed a weaker effect. We observed the same effect of canagliflozin for the intracellular recovery of Salmonella Typhimurium strain LT2 from uroepithelial cells, an invasive pathogen that employs different invasion mechanisms than UPEC. The effect of canagliflozin on the recovery of intracellular UPEC and Salmonella was cell type-dependent and was observed in uroepithelial cell lines and macrophage-like THP-1 cells, but not in human colorectal adenocarcinoma-derived Caco-2 cells. Additionally, several SGLT2 inhibitors interfered with hemolysis. Taken together, canagliflozin demonstrated activity against UPEC regarding intracellular bacterial numbers and hemolytic activity in vitro, suggesting novel avenues for UTI treatment. Targeting the pore-forming toxin α-hemolysin and reducing the number of intracellular UPEC may offer a potential complementary strategy to antibiosis in combating recurrent UTI.