The study shows that MRSA bacteria with the cfr gene are tougher against the body’s natural peptide LL‑37 and antibiotics, making infections harder to treat. Using the antibiotic linezolid together with rifampicin works much better than linezolid alone, cutting the needed dose and improving outcomes in mouse infection models. This finding is mainly relevant for clinical treatment, not for DIY health hacks.

Linezolid resistance mediated by the <i>cfr</i> gene in MRSA represents a global concern. We investigated relevant phenotype differences between <i>cfr</i>-positive and -negative MRSA that contribute to pathogenesis, and the efficacy of linezolid-based combination therapies in murine models of bacteremia and skin and skin structure infection (SSSI). As a group, <i>cfr</i>-positive MRSA exhibited significantly reduced susceptibilities to the host defense peptides tPMPs, human neutrophil peptide-1 (hNP-1), and cathelicidin LL-37 (<i>P</i> &lt; 0.01). In addition, increased binding to fibronectin (FN) and endothelial cells paralleled robust biofilm formation in <i>cfr</i>-positive vs. -negative MRSA. <i>In vitro</i> phenotypes of <i>cfr</i>-positive MRSA translated into poor outcomes of linezolid monotherapy <i>in vivo</i> in murine bacteremia and SSSI models. Importantly, rifampicin showed synergistic activity as a combinatorial partner with linezolid, and the EC₅₀ of linezolid decreased 6-fold in the presence of rifampicin. Furthermore, this combination therapy displayed efficacy against <i>cfr</i>-positive MRSA at clinically relevant doses. Altogether, these data suggest that the use of linezolid in combination with rifampicin poses a viable therapeutic alternative for bacteremia and SSSI caused by <i>cfr</i>-positive multidrug resistant MRSA.