Structural and Biochemical Studies of Dihydrofolate Reductase fromStreptococcus pyogenesas a Target for Antifolate Antibiotics

Streptococcus pyogenes, abeta-hemolytic bacterium, causes a wide spectrum of infections in human including pharyngitis, tonsillitis, scarlet fever, rheumatic fever, and necrotizing fasciitis. Streptococcal infections can also exist as co-infection with methicillin resistantStaphylococcus aureus(MRSA). Trimethoprim-sulfamethoxazole (TMP-SMX) combination has been used for treatment ofS. pyogenesand MRSA co-infection. However, resistance to TMP, an inhibitor of dihydrofolate reductase enzyme (DHFR), has challenged the efficacy of TMP-SMX combination. We explored the activity of a series of novel DHFR inhibitors againstS. pyogenes. This study identified potent inhibitors of DHFR enzyme fromS. pyogeneswith excellent inhibitory activity against the growth of the live bacteria. We determined, for the first time, the crystal structure ofS. pyogenesDHFR which provides structural insights into design and development of antifolate agents against this global pathogen.