The synoxazolidinone family of natural products was reported to have antimicrobial activity against Gram positive bacteria including Staphylococcus aureus. We previously reported the total synthesis of synoxazolidinones A and B and a set of analogs that revealed dichlorinated analogs with potent anti-biofilm activity against methicillin-resistant Staphylococcus aureus (MRSA). Bacterial biofilms are implicated in up to 80% of chronic bacterial infections, and can be up to 1000 times more resistant to antibiotics compared to planktonic bacteria. Even though biofilms have been implicated for decades, there remain no FDA-approved drugs that target biofilms. In this presentation, a new series of synoxazolidinone analogs was prepared in order to expand the anti-biofilm SAR. Among the analogs prepared, six compounds were identified that significantly inhibit biofilms as well as three compounds that have improved MIC values relative to the natural product. The most potent biofilm inhibitors were screened for biofilm dispersal. Finally, the biofilm inhibitors identified in the initial assays were tested in a mature biofilm assay in which the biofilms were grown on a collagen matrix for 48 hours. Our lead analogs were found to significantly reduce the amount of viable bacteria in the biofilm, and displayed significant synergism with first-line antibiotics.

Synthesis and evaluation of 4-oxazolidinones as Staphylococcus aureus biofilm modulating agents

2019 Fall National Meeting

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