Fosmidomycin (sodium salt) is a specific inhibitor of 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXP)[1]. Fosmidomycin is a phosphate antibiotic isolated from Streptomyces that is active against both Gram-negative and Gram-positive bacteria[2]. Fosmidomycin is an effective and safe antimalarial drug[3]. Fosmidomycin inhibits the second reaction in the non-mevalonate pathway of isoprene biosynthesis, which is an important pathway for many obligate intracellular pathogens, including mycobacteria and apicomplexan parasites[4].
In vitro, Escherichia coli cells treated with Fosmidomycin (0-100µM) for 24-72h developed resistance to Fosmidomycin within 24h, and resistance developed more rapidly at lower concentrations[5]. Fosmidomycin (0.25-2mM) treatment of HeLa cells infected with Chlamydia does not inhibit the ability of Chlamydia to infect HeLa cells, but it does prevent the development and production of inclusion bodies in infectious offspring[6].
In vivo, Fosmidomycin (75mg/kg) was administered orally to treat mice infected with Plasmodium vinckei for 2 days and effectively treated the parasitemia of mice. The effect was better when combined with clindamycin[7].
References:
[1] Kuzuyama T, Shimizu T, Takahashi S, et al. Fosmidomycin, a specific inhibitor of 1-deoxy-D-xylulose 5-phosphate reductoisomerase in the nonmevalonate pathway for terpenoid biosynthesis[J]. Tetrahedron letters, 1998, 39(43): 7913-7916.
[2] Parkinson E I, Erb A, Eliot A C, et al. Fosmidomycin biosynthesis diverges from related phosphonate natural products[J]. Nature chemical biology, 2019, 15(11): 1049-1056.
[3] Missinou M A, Borrmann S, Schindler A, et al. Fosmidomycin for malaria[J]. The Lancet, 2002, 360(9349): 1941-1942.
[4] Sparr C, Purkayastha N, Kolesinska B, et al. Improved efficacy of fosmidomycin against Plasmodium and Mycobacterium species by combination with the cell-penetrating peptide octaarginine[J]. Antimicrobial agents and chemotherapy, 2013, 57(10): 4689-4698.
[5] Hemmerlin A, Tritsch D, Hammann P, et al. Profiling of defense responses in Escherichia coli treated with fosmidomycin[J]. Biochimie, 2014, 99: 54-62.
[6] Slade J A, Brockett M, Singh R, et al. Fosmidomycin, an inhibitor of isoprenoid synthesis, induces persistence in Chlamydia by inhibiting peptidoglycan assembly[J]. PLoS pathogens, 2019, 15(10): e1008078.
[7] Wiesner J, Henschker D, Hutchinson D B, et al. In vitro and in vivo synergy of fosmidomycin, a novel antimalarial drug, with clindamycin[J]. Antimicrobial Agents and Chemotherapy, 2002, 46(9): 2889-2894.
Fosmidomycin (sodium salt)是1-脱氧-d-木酮糖5-磷酸还原异构酶（DXP）的特异性抑制剂[1]。Fosmidomycin是一种从链霉菌属细菌中分离出来的磷酸抗生素，对革兰氏阴性菌和革兰氏阳性菌均有活性[2]。Fosmidomycin是一种有效且安全的抗疟药[3]。Fosmidomycin能够抑制异戊二烯生物合成的非甲羟戊酸途径中的第二个反应，该途径是许多专性细胞内病原体（包括分枝杆菌和顶复门寄生虫）的重要途径[4]。
在体外，Fosmidomycin（0-100µM）处理大肠杆菌细胞24-72h，在24小时内细胞就对磷胺霉素产生了抗性，且浓度越低抗性出现得越快[5]。Fosmidomycin（0.25-2mM）处理感染了衣原体的HeLa细胞，不会抑制衣原体感染HeLa细胞的能力，但会阻止感染性后代的包涵体发育和产生[6]。
在体内，Fosmidomycin（75mg/kg）通过口服给药治疗文氏疟原虫（Plasmodium vinckei）感染小鼠2天，有效治疗了小鼠的寄生虫血症，与克林霉素联合治疗效果更佳[7]。