Optimization of methionyl tRNA-synthetase inhibitors for treatment of Cryptosporidium infection.

Optimization of methionyl tRNA-synthetase inhibitors for treatment of Cryptosporidium infection. Antimicrob Agents Chemother. 2019 Feb 11;: Authors: Buckner FS, Ranade RM, Gillespie JR, Shibata S, Hulverson MA, Zhang Z, Huang W, Choi R, Verlinde CLMJ, Hol WGJ, Ochida A, Akao Y, Choy RKM, Van Voorhis WC, Arnold SLM, Jumani RS, Huston CD, Fan E Abstract Cryptosporidiosis is one of the leading causes of moderate to severe diarrhea in children in low-resource settings. The therapeutic options for cryptosporidiosis are limited to one drug, nitazoxanide, which unfortunately has poor activity in the most needy populations of malnourished children and HIV infected persons. This paper describes the discovery and early optimization of a class of imidazopyridine-containing compounds with potential for treating Cryptosporidium infections. The compounds target the Cryptosporidium methionyl-tRNA synthetase (MetRS), an enzyme that is essential for protein synthesis. The most potent compounds inhibited the enzyme with Ki values in the low picomolar range. Cryptosporidium cells in culture were potently inhibited with EC50 values as low 7 nM and >1000-fold selectivity over mammalian cells. A parasite persistence assay indicates that the compounds act by a parasiticidal mechanism. Several compounds were demonstrated to control infection in two murine models of cryptosporidiosis without evidence of toxicity. Pharmacological and physicochemical charac...
Source: Antimicrobial Agents and Chemotherapy - Category: Microbiology Authors: Tags: Antimicrob Agents Chemother Source Type: research