Ion pairing to enhance antibiotic drug efficacy. A new approach to fight problematic infections?

Background The worldwide increased burden of bacterial resistance urges novel approaches to enhance control and treatment. It is estimated that only in Europe one million resistant strains related deaths will be recorded by 2025. We propose ion pairing as a tool to enhance antibiotic drug efficacy against problematic lung infections, e.g. Tuberculosis. Methods Amikacin and kanamycin were ion paired with dehoxycholic acid (DCA) and vancomycin with ursodehoxycholic acid (UDCA) in green conditions at different stoichiometry ratios. The new compounds were characterized by DSC, FTIR, UV-vis spectrophotometry, molecular modeling and NMR. The minimum inhibition concentration (MIC) was measured on sensitive Staphilococcus aureus and clinical isolates of methicillin resistant S. aureus (MRSA). The inhibition capacity and activity on MSRA biofilms were also measured and morphologically investigated by fluorescence microscopy. Results The ion pairs formed spontaneously with high yield at 1:4, 1:3 and 2:1 ratios for amikacin, kanamycin and vancomycin, respectively. Both DCA and UDCA showed high binding affinity with the respective drugs and the structures were partially resolved by combining in silico modeling and NMR analysis. The activity of the ion pairs was 5 to 10 fold higher than that of the parent drugs. Higher inhibition as well as enhanced efficacy in the treatment of established MSRA biofilms was observed. Conclusions The enhanced efficacy on MRSA biofilms suggests that ion pairing may result an important platform to improve the treatment and control of problematic infectious diseases. This strategy possesses two intrinsic advantages:1) a likely faster bench-to-market pathway, 2) easy formulation as dry powder to allow inhalation.