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Infections caused by multidrug-resistant enterococci, particularly vancomycin-resistant (VRE), present significant therapeutic challenges. Daptomycin, a last-line treatment for VRE, often loses efficacy due to the emergence of resistance. In this study, we revealed the critical role of the gene as a key determinant of daptomycin susceptibility and resistance in . We showed that in the absence of a functional , daptomycin-resistant mutants did not emerge , and derivatives of clinical daptomycin-resistant strains engineered to lack functional were rendered even more sensitive to daptomycin than wild-type daptomycin-susceptible strains. These findings indicated that functional is critical for key known mechanisms of daptomycin resistance, and mutations in have phenotypic dominance to those that otherwise confer resistance. Therefore, inhibiting the activity of the gene product is predicted to prevent or reverse resistance, offering a promising new strategy for extending the efficacy of daptomycin for treating enterococcal infections.IMPORTANCEDaptomycin is one of the few remaining effective antibiotics for treating vancomycin-resistant enterococcal infections but is limited by the emergence of resistance during protracted therapy. Here, we show that without a functional gene, daptomycin-resistant mutants do not arise under conditions where wild-type strains readily generate daptomycin-resistant mutants. Furthermore, we show that loss of function mutation of the gene in daptomycin-resistant clinical isolates renders them more susceptible to daptomycin than wild-type . This indicates that an effective small molecule inhibitor of LafB activity or gene expression would be a useful adjunctive for extending and restoring the therapeutic utility of daptomycin.