Drosophila melanogaster as a function-based high-throughput screening model for anti-nephrolithiasis agents in kidney stone patients

Abstract

Kidney stone disease involves the aggregation of stone-forming salts consequent to solute supersaturation in urine. The development of novel therapeutic agents for this predominantly metabolic and biochemical disorder have been hampered by the lack of a practical pre-clinical model amenable to drug screening. Here, Drosophila melanogaster, an emerging model for kidney stone disease research, was adapted as a high throughput functional drug screening platform agnostic of the multifactorial nature of mammalian nephrolithiasis. Through functional screening, the therapeutic potential of a novel compound commonly known as Arbutin that specifically binds to oxalate, a key component of kidney calculi, was identified. Through isothermal titration calorimetry, high performance liquid chromatography and atomic force microscopy, Arbutin was determined to interact with calcium and oxalate in both free and bound states, disrupting crystal lattice structure, growth and crystallization. Patient urine samples treated with Arbutin significantly abrogated calculus formation in vivo and outperformed potassium citrate in low pH urine conditions due to its oxalate-centric mode of action. The discovery of this novel anti-lithogenic compound via D. melanogaster independent of a mammalian model brings greater recognition to this platform where metabolic features are primary outcomes, underscoring the power of D. melanogaster as a high throughput drug screening platform in similar disorders. This is the first description of the use of D. melanogaster as the model system for a high-throughput chemical library screen.