Micellar curcumin improves the antibacterial activity of the alkylphosphocholines erufosine and miltefosine against pathogenic Staphyloccocus aureus strains

In the light of the emerging bacterial resistance to broad-spectrum antibiotics, the search for new antibacterial therapeutics and drug combinations is one of the most challenging topics nowadays. In the present study, we investigated for the first time the antibacterial and biofilm inhibitory effects of the third generation anticancer alkylphosphocholine (APC) erufosine against pathogenic Staphylococcus aureus strains in comparison to the prototype of this pharmacological class of drugs, miltefosine. We also searched for synergistic antibacterial combinations between both APCs and curcumin incorporated in copolymeric micelles based on Pluronic® P123 or a mixture of Pluronic ® P123 and Pluronic ® F127 (P123/F127). The obtained quantitative redox-activity experimental data and drug-drug interactions were evaluated by using mathematical models in the MAPLE software. Similar to miltefosine, erufosine showed a moderate bacteriostatic effect in clinically relevant concentrations (50 ÷ 60 µmol/L) and inhibited the redox activity of the treated bacteria up to 90% at minimal inhibitory concentrations. The effect of both APCs towards methicillin resistant staphylococci was enhanced by combinations with P123/F127 micellar CRM at a ratio of 1:1. Erufosine showed a stronger median biofilm inhibition at lower concentrations (MBIC 50 = 1.87 µmol/L) than miltefosine (MBIC 50 = 6.0 µmol/L) and curcumin (MBIC 50 = 24.84 µmol/L) as demonstrated by quantification of biofilm-bound bacteria. In conclusion, the estimated antibacterial activity of erufosine widens the spectrum of its useful pharmacological effects, which is important for its clinical development. The established synergistic and additive drug combinations could be beneficial for the application of both APCs in cancer therapy, since numerous malignancies are accompanied by bacterial infections.