Bacterial biofilms are surface-attached bacterial communities that occur in ~80% of all bacterial infections. Biofilm-associated infections are highly resistant to our current arsenal of antibiotics. Staphylococcus aureus and Staphylococcus epidermidis are major human pathogens recognized as the most frequent cause of biofilm-associated nosocomial and indwelling medical device infections. To make matters worse, very few chemotypes exist that target Staphylococcal biofilms. Our group recently synthesized a phenazine antibiotic-inspired, focused library of diverse phenazine small molecules which were evaluated against Staphylococcal bacteria for antibacterial and antibiofilm activities. From these investigations, our group discovered several potent halogenated phenazines that demonstrate potent antibacterial and antibiofilm activity against methicillin-resistant S. aureus and S. epidermidis. Using a scaffold hopping strategy from the active 1-hydroxy-2,4-dibromophenazine scaffold, we synthesized and evaluated a focused library of 5,7-dihalo-8-hydroxyquinoline small molecules that also demonstrate potent antibacterial and antibiofilm activities against Staphylococcus biofilms. These important discoveries have the potential to provide clinically effective treatment options for patients suffering from drug-resistant, biofilm-associated Staphylococcal infections.

Discovery of halogenated phenazine and halogenated quinoline small molecules with antibacterial and antibiofilm activities against staphylococcal biofilms

249th National Meeting (2015)

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