Cyclo-glycylproline, a food-derived diketopiperazine, inhibits bacterial indole production: implications for diabetic nephropathy prevention

Diabetic nephropathy is a kidney disease aggravated by the uremic toxin indoxyl sulfate, which is produced from indole by the gut microbiota. Targeting the bacterial enzyme tryptophan indole-lyase (TIL), which produces indole from l-tryptophan, could be a promising therapeutic strategy. This study investigates diketopiperazines (DKPs), particularly cyclo-glycylproline [cyclo(Gly-Pro)], as potential TIL inhibitors. Cyclo(Gly-Pro) and other DKPs moderately inhibited indole production from l-tryptophan in crude bacterial extracts. Cyclo(Gly-Pro) was not metabolized by the bacteria and did not affect their viability. Cyclo(Gly-Pro) inhibited the Escherichia coli TIL with a Ki​ value of 17 μM through a mixed-type mechanism. Computational docking studies supported this finding, showing that cyclo(Gly-Pro) binds near the active site of TIL. Additionally, cyclo(Gly-Pro) significantly reduced indole production in bacterial cultures and human fecal samples. These findings suggest that cyclo(Gly-Pro) could be a promising dietary supplement or a lead compound for developing new therapeutics to prevent or treat diabetic nephropathy.