Therapeutics: Dehydrosqualene desaturase (CrtN)

In vitro, human blood and mouse studies identified a Naftin naftifine-derived CrtN inhibitor that could help treat methicillin-resistant Staphylococcus aureus (MRSA) infection. Chemical synthesis and testing of benzofuran analogs of Naftin identified a compound that inhibited the enzymatic activity of CrtN with an IC50 of 338.8 nM in vitro and inhibited CrtN-mediated biosynthesis of the antioxidant staphyloxanthin with an IC50 of 3.93 nM in S. aureus culture. In three strains of MRSA, the compound inhibited proliferation with IC50 values of 0.38-5.45 nM. In human whole blood samples infected with the three MRSA strains, the compound decreased bacterial survival compared with vehicle. In mouse models infected with the three MRSA strains, the compound decreased bacterial burden in the kidney, liver and/or heart. Next steps include testing the CrtN inhibitor in additional models of MRSA infection...