Treating the untreatable: Reversing β-lactam resistance in MRSA by membrane-domain-dissolving antibiotics

Antimicrobial resistance is one of the most serious threats to global health with methicillin-resistant Staphylococcus aureus (MRSA) being the leading Gram-positive pathogen. Recently we discovered a new antimicrobial target for small antibiotics — dissolution of functional domains in the bacterial membrane without pore formation. Here we apply this mechanism to reverse β-lactam resistance in MRSA. We show that supplementation with a membrane-domain-dissolving antibiotic lowers the susceptibility of both a MRSA clinical isolate and the methicillin-susceptible S. aureus (MSSA) to multiple β-lactams several folds. In particular, full reversal of resistance to oxacillin and penicillin in MRSA is achieved. We provide evidence on the nano-scale (atomic force microscopy), living bacteria (fluorescence microscopy), and bacterial cultures (microbiology assays) that the β-lactam resistance reversal is linked to dissolution of membrane domains. A general nature of this principle is expected, and could be applied using various membrane-domain-dissolving antibiotics to reverse β-lactam resistance in various bacteria.