In vitro activities of three new dihydrofolate reductase inhibitors against clinical isolates of gram-positive bacteria.

BAL0030543, BAL0030544, and BAL0030545 are dihydrophthalazine inhibitors with in vitro potency against gram-positive pathogens. The MIC(50)s for methicillin (meticillin)-sensitive Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, hetero-vancomycin-resistant Staphylococcus aureus, and vancomycin-resistant Staphylococcus aureus (VISA) range from 0.015 to 0.25 microg/ml (MIC(90)s < or = 0.5 microg/ml). MIC(50)s for beta-hemolytic streptococci range from 0.03 to 0.06 microg/ml, MIC(50)s for Streptococcus pneumoniae range from 0.06 to 0.12 microg/ml, MIC(50)s for Listeria monocytogenes range from 0.015 to 0.06 microg/ml, and MIC(50)s for Streptococcus mitis are < or = 0.015 microg/ml. These three dihydrophthalazine antifolates have improved potency compared to that of trimethoprim and activity against gram-positive pathogens resistant to other drug classes. (This work was presented in part at the 48th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, 2008.).