Tricyclic amine antidepressants suppress β‐lactam resistance in methicillin‐resistant Staphylococcus aureus (MRSA) by repressing mRNA levels of key resistance genes

Abstract Methicillin‐resistant Staphylococcus aureus ( MRSA ) is the leading cause of recurrent infections in humans including endocarditis, pneumonia, and toxic shock syndrome. Novel therapeutics to treat MRSA and other resistant bacteria are urgently needed. Adjuvant therapy, which uses a non‐toxic compound to repotentiate the toxic effects of an existing antibiotic, is an attractive response to the growing resistance crisis. Herein, we describe the evaluation of structurally related, FDA ‐approved tricyclic amine antidepressants that selectively repotentiate MRSA to β‐lactam antibiotics. Our results identify important structural features of the tricyclic amine class for β‐lactam adjuvant activity. Furthermore, we describe the mechanism of action for our lead compound, amoxapine, and illustrate that it represses the mRNA levels of key β‐lactam resistance genes in response to β‐lactam treatment. This work is novel in that it highlights an important class of small molecules with the ability to simultaneously inhibit production of both β‐lactamase and penicillin binding protein 2a.