Project Grant R03DK149104

The National Institute of Diabetes and Digestive and Kidney Diseases awarded The Trustees of Columbia University in the City of New York $123,375 on August 20, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to conduct structure-guided research aimed at preventing polymyxin-induced acute kidney injury.

The project will characterize the interaction between polymyxin B and the endocytic receptor LRP2/megalin using cross-linking mass spectrometry and single-particle cryo-electron microscopy to map binding sites and visualize the drug-receptor complex. Structural findings will inform an in silico screen for small-molecule competitive inhibitors of the LRP2-polymyxin interaction. The most promising candidates will be validated through surface plasmon resonance competition assays. The research addresses a critical clinical need: polymyxin B serves as a last-line therapy for life-threatening multidrug-resistant gram-negative infections but causes dose-limiting nephrotoxicity driven by its accumulation in kidney proximal tubule cells through LRP2-mediated endocytosis. Blocking this interaction is hypothesized to uncouple the antibiotic's antimicrobial activity from its renal toxicity, making the drug safer for critically ill patients.

Performance occurs in New York, New York 10032. The period of performance runs through June 30, 2028. The award is classified as a Project Grant, an assistance type supporting research activities at universities and research institutions.