title: Carnosic acid is an efflux pumps modulator by dissipation of the membrane potential in Enterococcus faecalis and Staphylococcus aureus.
abstract: Bacterial resistance to antibiotics has become a serious problem of public health. Along with the controlled permeability by the cell-wall, active efflux systems can provide resistance by extruding antibiotics. Carnosic acid is capable to potentiate the antimicrobial activity of several antibiotics. However, the underlying molecular mechanism governing this effect remains unclear. The present study aims to investigate the effect of carnosic acid on the transport of ethidium bromide, on the permeability or the membrane potential in Enterococcus faecalis and Staphylococcus aureus. By using fluorimetric assays it was demonstrated that in E. faecalis, carnosic acid is a modulator of the uptake and efflux of ethidium bromide which does not induce cell membrane permeabilization phenomena. Such effect was sensitive to the inhibition caused by both the proton-motive force carbonyl cyanide m-chlorophenylhydrazone and the calcium antagonist verapamil, but not to vanadate, an ATPase inhibitor. In this work it was demonstrated, for the first time, that the activity of carnosic acid on the uptake/efflux of ethidium bromide is correlated with its capacity to change the membrane potential gradient in S. aureus and E. faecalis. In conclusion, carnosic acid is a natural compound, structurally unrelated to known antibiotics, which can function as an efflux pump modulator by dissipation of the membrane potential. Therefore, carnosic acid would be a good candidate to be employed as a novel therapeutic agent to be used in combination therapies against drug-resistant enterococci and S. aureus infections.
authors.affiliation: Laboratory of Plant Biochemistry, Fundación Instituto Leloir, Instituto de Investigaciones Bioquímicas Buenos Aires I.I.B.B.A-CONICET, Av Patricias Argentinas 435, C1405BWE, Ciudad Autónoma de Buenos Aires, Argentina.
authors.forename: Adriana M
authors.initials: AM
authors.lastname: Ojeda-Sana
authors.forename: Victoria
authors.initials: V
authors.lastname: Repetto
authors.forename: Silvia
authors.initials: S
authors.lastname: Moreno
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D024901:Drug Resistance, Multiple, Bacterial; D013293:Enterococcus faecalis / Q000187:drug effects* / Q000378:metabolism; D004996:Ethidium / Q000378:metabolism / Q000493:pharmacokinetics; D008564:Membrane Potentials / Q000187:drug effects; D010539:Permeability / Q000187:drug effects; D010936:Plant Extracts / Q000494:pharmacology*; D018892:Proton-Motive Force / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000378:metabolism
chemical_list: D045784:Abietanes; D000900:Anti-Bacterial Agents; D010936:Plant Extracts; D004996:Ethidium; C018381:salvin