Chemical Modification of Tiopronin for Dual Management of Cystinuria and Associated Bacterial Infections

Cystinuria is an inherited autosomal recessive disease of the kidneys of recurring nature that contributes to frequent urinary tract infections due to bacterial growth and biofilm formation surrounding the stone microenvironment. In the past, commonly used strategies for managing cystinuria involved the use of (a) cystine crystal growth inhibitors such as l-cystine dimethyl ester and lipoic acid, and (b) thiol-based small molecules such as N-(2-mercaptopropionyl) glycine, commonly known as tiopronin, that reduce the formation of cystine crystals by reacting with excess cystine and generating more soluble disulfide compounds. However, there is a dearth of simplistic chemical approaches that have focused on the dual treatment of cystinuria and the associated microbial infections. This work strategically exploited a single chemical approach to develop a nitric oxide (NO)-releasing therapeutic compound, S-nitroso-2-mercaptopropionyl glycine (tiopronin-NO), for the dual management of cystine stone formation and the related bacterial infections. The results successfully demonstrated that (a) the antibacterial activity of NO rendered tiopronin-NO effective against the stone microenvironment inhabitants, Escherichia coli and Pseudomonas aeruginosa, and (b) tiopronin-NO retained the ability to undergo disulfide exchange with cystine while being reported to be safe against canine kidney and mouse fibroblast cells. Thus, the synthesis of such a facile molecule aimed at the dual management of cystinuria and related infections is unprecedented in the literature.

Automated summary

Cystinuria is an inherited disease that causes recurring kidney problems and frequent urinary tract infections. Previous strategies for managing cystinuria focused on inhibiting cystine crystal growth and reducing the formation of cystine crystals. However, there has been a lack of chemical approaches that can effectively treat both cystinuria and associated infections. This study developed a nitric oxide-releasing compound, tiopronin-NO, which showed antibacterial activity against the bacteria in the stone microenvironment and retained the ability to react with cystine. This synthesis of a dual management molecule for cystinuria and bacterial infections is unprecedented.