Synthetic antibiotics and antimicrobial agents, such as sulfonamide and triclosan (TCS), have provided new avenues in the treatment of bacterial infections, as they target lethal intracellular pathways. Sulfonamide antibiotics block synthesis of folic acid by inhibiting dihydrofolate reductase (DHFR) while TCS block fatty acid synthesis through inhibition of enoyl-ACP reductase (FabI). They are water-insoluble agents and high doses are toxic, limiting their therapeutic efficiency. In this study, an antibiotic drug-targeting strategy based on utilizing ovotransferrin (OTf) as a carrier to allow specific targeting of the drug to microbial or mammalian cells via the transferrin receptor (TfR) is explored, with potential to alleviate insolubility and toxicity problems. Complexation, through non-covalent interaction, with OTf turned sulfa antibiotics or TCS into completely soluble in aqueous solution. OTf complexes showed superior bactericidal activity against several bacterial strains compared to the activity of free agents. Strikingly, a multi-drug resistant Salmonella strain become susceptible to antibiotics-OTf complexes while a tolC-knockout mutant strain become susceptible to OTf and more sensitive to the complexes. The antibiotic bound to OTf was, thus exported through the multi-drug efflux pump TolC in Salmonella wild-type strain. Further, antibiotics-OTf complexes were able to efficiently kill intracellular pathogens after infecting human colon carcinoma cells (HCT-116). The results demonstrate, for the first time, that the TfR mediated endocytosis of OTf can be utilized to specifically target drugs directly to pathogens or intracellularly infected cells and highlights the potency of the antibiotic-OTf complex for the treatment of infectious diseases.
