Exploration of a benzothiophene scaffold for use as adjuvants with β-lactam antibiotics against methicillin-resistant Staphylococcus aureus

Abstract

Rising antibiotic resistance coupled with diminishing investment in antibiotic development has led to limited treatment options for multi drug-resistant bacterial infections. Penicillin binding protein 2a (PBP2a) is a key determinant of resistance to many β-lactam antibiotics in methicillin-resistant Staphylococcus aureus (MRSA), while over-expression of PBP4 mediates resistance to fifth-generation cephalosporins. We previously identified benzothiophene NDM-335 as an inhibitor of PBP4 that overcomes PBP4 mediated resistance to ceftobiprole, and have shown that other PBP4 inhibitor scaffolds can be tuned to overcome PBP2a-mediated resistance. Based upon this precedent, we conducted a structure activity relationship (SAR) study on the NDM-335 scaffold to uncover compounds that overcome PBP2a-mediated oxacillin resistance in MRSA, with the lead compound lowering the minimum inhibitory concentration 32-fold at 5 μM. Further development of this new adjuvant lead could potentially deliver a new combination therapy for treating MRSA infections.