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bioRxiv · 10.1101/2025.10.27.684379

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

Melcrova, A.·Woudstra, W.·Wenzel, M.·Gabler, M.·Stensen, W.·Svendsen, J.·Roos, W.·Schirhagl, R.
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Abstract

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 {beta}-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 {beta}-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 {beta}-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 {beta}-lactam resistance in various bacteria. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=85 SRC="FIGDIR/small/684379v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@1608f24org.highwire.dtl.DTLVardef@55b460org.highwire.dtl.DTLVardef@b54337org.highwire.dtl.DTLVardef@4fef04_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOTOC Figure:C_FLOATNO Model of -lactam susceptibility renewal in MRSA based on data presented in this study. C_FIG

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Melcrova, A., Woudstra, W., Wenzel, M., Gabler, M., Stensen, W., Svendsen, J., Roos, W., Schirhagl, R.. 2025-10-27. Treating the untreatable: Reversing β-lactam resistance in MRSA by membrane-domain-dissolving antibiotics. https://doi.org/10.1101/2025.10.27.684379

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