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NH125 kills methicillin-resistant Staphylococcus aureus persisters by lipid bilayer disruption

    Wooseong Kim

    Division of Infectious Diseases, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, USA

    ,
    Nico Fricke

    School of Engineering, Brown University, Providence, RI, USA

    ,
    Annie L Conery

    Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA

    Department of Genetics, Harvard Medical School, Boston, MA, USA

    ,
    Beth Burgwyn Fuchs

    Division of Infectious Diseases, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, USA

    ,
    Rajmohan Rajamuthiah

    Division of Infectious Diseases, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, USA

    Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA

    ,
    Elamparithi Jayamani

    Division of Infectious Diseases, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, USA

    Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA

    ,
    Petia M Vlahovska

    School of Engineering, Brown University, Providence, RI, USA

    ,
    Frederick M Ausubel

    Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA

    Department of Genetics, Harvard Medical School, Boston, MA, USA

    &
    Eleftherios Mylonakis

    *Author for correspondence:

    E-mail Address: eleftherios_mylonakis@brown.edu

    Division of Infectious Diseases, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, USA

    Published Online:https://doi.org/10.4155/fmc.15.189

    Background: NH125, a known WalK inhibitor kills MRSA persisters. However, its precise mode of action is still unknown. Methods & results: The mode of action of NH125 was investigated by comparing its spectrum of antimicrobial activity and its effects on membrane permeability and giant unilamellar vesicles (GUVs) with walrycin B, a WalR inhibitor and benzyldimethylhexadecylammonium chloride (16-BAC), a cationic surfactant. NH125 killed persister cells of a variety of Staphylococcus aureus strains. Similar to 16-BAC, NH125 killed MRSA persisters by inducing rapid membrane permeabilization and caused the rupture of GUVs, whereas walrycin B did not kill MRSA persisters or induce membrane permeabilization and did not affect GUVs. Conclusion: NH125 kills MRSA persisters by interacting with and disrupting membranes in a detergent-like manner.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

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