Each year over 20,000 people die from methicillin-resistant Staphylococcus aureus (MRSA) infections. MRSA is particularly difficult to treat because it employs virulence behaviors, such as biofilm formation and antibiotic resistance, which allow it to evade many common therapies. We have previously reported ß-lactam antibiotic potentiation in MRSA by a class of structurally related tetracyclic amines. These compounds act via a non-toxic mechanism and show promise for further synthetic development as antibiotic adjuvants. To direct our synthetic efforts, we employed a fragment based screening strategy to generate a preliminary structure activity relationship. Our screening program identified several structural features necessary for adjuvant activity in MRSA and have led to the identification of a putative pharmacophore. These data along with ligand efficiency analyses and mechanism of action studies will be presented.

Identification of a pharmacophore capable of potentiating ß-lactam antibiotics in methicillin-resistant Staphylococcus aureus (MRSA) via fragment based screening

255th National Meeting (2018)

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