Ibrahim Hisham R, Tatsumoto Sayuri, Ono Hajime, Van Immerseel Filip, Raspoet Ruth, Miyata Takeshi
Department of Biochemistry and Biotechnology, Faculty of Agriculture, Kagoshima University, Kagoshima 890-0065, Japan.
Department of Biochemistry and Biotechnology, Faculty of Agriculture, Kagoshima University, Kagoshima 890-0065, Japan.
Eur J Pharm Sci. 2015 Jan 23;66:59-69. doi: 10.1016/j.ejps.2014.10.005. Epub 2014 Oct 12.
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.
合成抗生素和抗菌剂，如磺胺类药物和三氯生（TCS），为细菌感染的治疗提供了新途径，因为它们针对致命的细胞内途径。磺胺类抗生素通过抑制二氢叶酸还原酶（DHFR）来阻断叶酸的合成，而三氯生则通过抑制烯酰-ACP还原酶（FabI）来阻断脂肪酸的合成。它们是水不溶性药物，高剂量有毒，限制了它们的治疗效果。在本研究中，探索了一种基于利用卵转铁蛋白（OTf）作为载体的抗生素药物靶向策略，以使药物通过转铁蛋白受体（TfR）特异性靶向微生物或哺乳动物细胞，具有缓解不溶性和毒性问题的潜力。通过非共价相互作用与OTf络合，使磺胺类抗生素或TCS在水溶液中完全溶解。与游离药物相比，OTf络合物对几种细菌菌株表现出优异的杀菌活性。引人注目的是，一株多重耐药沙门氏菌菌株对抗生素-OTf络合物敏感，而一株tolC基因敲除突变菌株对OTf敏感且对络合物更敏感。因此，与OTf结合的抗生素通过沙门氏菌野生型菌株中的多药外排泵TolC排出。此外，抗生素-OTf络合物在感染人结肠癌细胞（HCT-116）后能够有效杀死细胞内病原体。结果首次证明，可以利用OTf的TfR介导的内吞作用将药物直接特异性靶向病原体或细胞内感染的细胞，并突出了抗生素-OTf络合物在治疗传染病方面的潜力。
