Purpose To investigate the role of dehoxycholic acid (DCA) in the improvement of antibiotic performance for a novel amikacin-dehoxycholic acid (A-DCA) insoluble ionic complex and to assess its in vivo toxicity. Methods Amikacin (A) was complexed with DCA by direct reaction in water at r.t.. The A-DCA dispersion activity was evaluated against S. aureus ATCC strain and clinical isolates of methicillin resistant S. aureus (MRSA) biofilms. The dispersion activity was also observed by scanning electron microscopy (SEM). The possible enhancer or carrier effect of DCA was evaluated by kinetic analysis of antibiofilm activity upon sequential addition of the compounds at different time intervals. Moreover, A-DCA stability upon dilution in water was investigated by conductivity measurements. The toxicity of the complex was investigated by the chicken embryo chorioallantoid membrane (CAM) assay. Results The A-DCA insoluble ionic complex is a 1:4 assembly of A with DCA. The A-DCA dispersion activity was 5 to 10 fold higher than that of the parent drug as reported earlier (1,2). Higher efficacy in the treatment of MSRA biofilms was observed. These findings were confirmed by SEM analysis. The kinetic profiles of biofilm dispersion obtained after sequential addition of DCA and A highlighted a certain enhancer action of DCA compared to the drug alone. However, the different kinetic profile of A-DCA suggested that the complex acts on the biofilm as a whole. As a check, conductivity analysis revealed stability of A-DCA upon dilution in water at concentrations well below the MIC. The complex resulted sufficiently safe as toxicity was comparable to that of the free drug and signs of damage on the CAM were observable only at 10xMIC concentration. Conclusions The A-DCA ionic complex results effective against S. aureus and resistant strain biofilms. DCA seems to exert a carrier effect as the complex was stable upon dilution and showed a kinetic activity profile different from the sequentially added free compounds. The sparingly adverse effects observed on the CAM may suggest a general safety of the complex in vivo.
Study on amikacin-dehoxycholic acid ionic complex antibiotic activity and toxicity: carrier or enhancer?
CECCARELLI, GIADA;PIETRELLA, Donatella;BARBERINI, Lanfranco;GIOVAGNOLI, Stefano
2016
Abstract
Purpose To investigate the role of dehoxycholic acid (DCA) in the improvement of antibiotic performance for a novel amikacin-dehoxycholic acid (A-DCA) insoluble ionic complex and to assess its in vivo toxicity. Methods Amikacin (A) was complexed with DCA by direct reaction in water at r.t.. The A-DCA dispersion activity was evaluated against S. aureus ATCC strain and clinical isolates of methicillin resistant S. aureus (MRSA) biofilms. The dispersion activity was also observed by scanning electron microscopy (SEM). The possible enhancer or carrier effect of DCA was evaluated by kinetic analysis of antibiofilm activity upon sequential addition of the compounds at different time intervals. Moreover, A-DCA stability upon dilution in water was investigated by conductivity measurements. The toxicity of the complex was investigated by the chicken embryo chorioallantoid membrane (CAM) assay. Results The A-DCA insoluble ionic complex is a 1:4 assembly of A with DCA. The A-DCA dispersion activity was 5 to 10 fold higher than that of the parent drug as reported earlier (1,2). Higher efficacy in the treatment of MSRA biofilms was observed. These findings were confirmed by SEM analysis. The kinetic profiles of biofilm dispersion obtained after sequential addition of DCA and A highlighted a certain enhancer action of DCA compared to the drug alone. However, the different kinetic profile of A-DCA suggested that the complex acts on the biofilm as a whole. As a check, conductivity analysis revealed stability of A-DCA upon dilution in water at concentrations well below the MIC. The complex resulted sufficiently safe as toxicity was comparable to that of the free drug and signs of damage on the CAM were observable only at 10xMIC concentration. Conclusions The A-DCA ionic complex results effective against S. aureus and resistant strain biofilms. DCA seems to exert a carrier effect as the complex was stable upon dilution and showed a kinetic activity profile different from the sequentially added free compounds. The sparingly adverse effects observed on the CAM may suggest a general safety of the complex in vivo.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
