Deletion of liar reverses daptomycin resistance in enterococcus faecium independent of the genetic background
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2015
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Antimicrobial agents and chemotherapy, 1098-6596, Vol. 59, Nro. 12, 2015, p. 7327-7334
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American Society for Microbiology
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Abstract
We have shown previously that changes in LiaFSR, a three-component regulatory system predicted to orchestrate the cell membrane stress response, are important mediators of daptomycin (DAP) resistance in enterococci. Indeed, deletion of the gene encoding the response regulator LiaR in a clinical strain of Enterococcus faecalis reversed DAP resistance (DAP-R) and produced a strain hypersusceptible to antimicrobial peptides. Since LiaFSR is conserved in Enterococcus faecium, we investigated the role of LiaR in a variety of clinical E. faecium strains representing the most common DAP-R genetic backgrounds. Deletion of liaR in DAP-R E. faecium R446F (DAP MIC of 16 Ī¼g/ml) and R497F (MIC of 24 Ī¼g/ml; harboring changes in LiaRS) strains fully reversed resistance (DAP MICs decreasing to 0.25 and 0.094 Ī¼g/ml, respectively). Moreover, DAP at concentrations of 13 Ī¼g/ml (achieved with human doses of 12 mg/kg body weight) retained bactericidal activity against the mutants. Furthermore, the liaR deletion derivatives of these two DAP-R strains exhibited increased binding of boron-dipyrromethene difluoride (BODIPY)-daptomycin, suggesting that high-level DAP-R mediated by LiaR in E. faecium involves repulsion of the calcium-DAP complex from the cell surface. In DAP-tolerant strains HOU503F and HOU515F (DAP MICs within the susceptible range but bacteria not killed by DAP concentrations of 5Ć the MIC), deletion of liaR not only markedly decreased the DAP MICs (0.064 and 0.047 Ī¼g/ml, respectively) but also restored the bactericidal activity of DAP at concentrations as low as 4 Ī¼g/ml (achieved with human doses of 4 mg/kg). Our results suggest that LiaR plays a relevant role in the enterococcal cell membrane adaptive response to antimicrobial peptides independent of the genetic background and emerges as an attractive target to restore the activity of DAP against multidrug-resistant strains.
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TemƔticas
Farmacorresistencia bacteriana
Daptomicina
Enterococcus faecium
Daptomicina
Enterococcus faecium