ETH-Zürich, Laboratorium für Organische Chemie, Departement für Chemie und Angewandte Biowissenschaften, Hönggerberg HCI, Zürich, Switzerland.
Antimicrob Agents Chemother. 2013 Oct;57(10):4689-98. doi: 10.1128/AAC.00427-13. Epub 2013 Jul 15.
Cellular drug delivery can improve efficacy and render intracellular pathogens susceptible to compounds that cannot permeate cells. The transport of physiologically active compounds across membranes into target cells can be facilitated by cell-penetrating peptides (CPPs), such as oligoarginines. Here, we investigated whether intracellular delivery of the drug fosmidomycin can be improved by combination with the CPP octaarginine. Fosmidomycin is an antibiotic that inhibits the second reaction in the nonmevalonate pathway of isoprenoid biosynthesis, an essential pathway for many obligate intracellular pathogens, including mycobacteria and apicomplexan parasites. We observed a strict correlation between octaarginine host cell permeability and its ability to improve the efficacy of fosmidomycin. Plasmodium berghei liver-stage parasites were only partially susceptible to an octaarginine-fosmidomycin complex. Similarly, Toxoplasma gondii was only susceptible during the brief extracellular stages. In marked contrast, a salt complex of octaarginine and fosmidomycin greatly enhanced efficacy against blood-stage Plasmodium falciparum. This complex and a covalently linked conjugate of octaarginine and fosmidomycin also reverted resistance of Mycobacteria to fosmidomycin. These findings provide chemical genetic evidence for vital roles of the nonmevalonate pathway of isoprenoid biosynthesis in a number of medically relevant pathogens. Our results warrant further investigation of octaarginine as a delivery vehicle and alternative fosmidomycin formulations for malaria and tuberculosis drug development.
细胞内药物递送可以提高疗效，并使细胞内病原体对不能穿透细胞的化合物敏感。亲脂性化合物通过细胞穿透肽（CPP），如寡聚精氨酸，穿过细胞膜进入靶细胞的运输可以得到促进。在这里，我们研究了与 CPP 八聚精氨酸结合是否可以提高福米霉素的细胞内递送。福米霉素是一种抗生素，它抑制异戊烯基生物合成的非甲羟戊酸途径中的第二个反应，该途径是许多必需的细胞内病原体（包括分枝杆菌和顶复门寄生虫）所必需的。我们观察到八聚精氨酸的宿主细胞通透性与其提高福米霉素疗效的能力之间存在严格的相关性。伯氏疟原虫肝期寄生虫仅对八聚精氨酸-福米霉素复合物部分敏感。同样，刚地弓形虫仅在短暂的细胞外阶段敏感。相比之下，八聚精氨酸和福米霉素的盐复合物大大增强了对恶性疟原虫血期的疗效。该复合物和八聚精氨酸与福米霉素的共价连接缀合物也使分枝杆菌对福米霉素的耐药性得到逆转。这些发现为异戊烯基生物合成的非甲羟戊酸途径在许多医学相关病原体中的重要作用提供了化学遗传证据。我们的结果证明，八聚精氨酸作为一种递药载体和福米霉素的替代制剂在疟疾和结核病药物开发中具有进一步研究的价值。
