BioCentury
ARTICLE | Distillery Therapeutics

Infectious disease

February 11, 2019 9:18 PM UTC

In vitro, cell culture, mouse, rat and dog studies identified a spiropyrimidinetrione-based bacterial DNA gyrase inhibitor that could help treat Staphylococcus, Streptococcus and other Gram-positive bacterial infections. Optimization and testing in bacterial growth assays of analogs of a previously reported spiropyrimidinetrione yielded a compound that inhibited S. aureus DNA gyrase in vitro with an IC50 of 7.8 μM. In bacterial cultures, the compound inhibited growth of multiple strains of methicillin-resistant Staphylococcus aureus (MRSA) with minimum inhibitory concentration (MIC) values of 0.03-0.125 mg/L; inhibited growth of methicillin-sensitive S. aureus (MSSA) and S. epidermidis, methicillin-resistant S. epidermidis, and Streptococcus pneumoniae and S. pyogenes with MIC values ≤ 0.03 mg/L; and inhibited growth of Neisseria gonorrhoeae with an MIC of 0.06 mg/L. In mouse models of systemic MRSA or MSSA infection, the compound prolonged survival with greater potency than the DNA gyrase and topoisomerase IV inhibitor zoliflodacin (effective doses: 3.87 vs. 11.51 mg/kg and 8.37 vs. 11.03 mg/kg, respectively). The compound had a plasma half-life of 6.2 hours in mice; a plasma half-life and oral bioavailability of 3.71 hours and 22.6%, respectively, in rats; and a plasma half-life and oral bioavailability of 3.65 hours and 96.6%, respectively, in dogs. Next steps could include testing the compound in animal models of additional Gram-positive bacterial infections...