Arca P, Rico M, Braña A F, Villar C J, Hardisson C, Suárez J E
Departamento de Biología Funcional, Facultad de Medicina, Universidad de Oviedo, Julian Clavería, Spain.
Antimicrob Agents Chemother. 1988 Oct;32(10):1552-6. doi: 10.1128/AAC.32.10.1552.
Plasmid-borne resistance to fosfomycin in bacteria is due to modification of the antibiotic molecule by a glutathione S-transferase that catalyzes the formation of a covalent bond between the sulfhydryl residue of the cysteine in glutathione and the C-1 of fosfomycin. This reaction results in opening of the epoxide ring of the antibiotic to form an inactive adduct, the structure of which was confirmed by nuclear magnetic resonance. Dialyzed extracts prepared from resistant Escherichia coli strains were unable to modify fosfomycin unless exogenous glutathione was added to the reaction mixtures. Similarly, mutants defective in glutathione biosynthesis were susceptible to fosfomycin, despite harboring a resistance plasmid. Extracts of resistant but not susceptible strains could join glutathione to 1-chloro-2,4-dinitrobenzene, confirming the nature of the enzymatic activity. Adduct formation appeared to be specific for glutathione: none of the other thiols tested (cysteine, N-acetylcysteine, and dithiothreitol) could modify fosfomycin.
细菌中质粒介导的对磷霉素的抗性是由于谷胱甘肽S-转移酶对抗生素分子进行修饰，该酶催化谷胱甘肽中半胱氨酸的巯基残基与磷霉素的C-1之间形成共价键。此反应导致抗生素的环氧环打开，形成无活性加合物，其结构通过核磁共振得以确认。除非向反应混合物中添加外源性谷胱甘肽，否则从耐药大肠杆菌菌株制备的透析提取物无法修饰磷霉素。同样，尽管携带抗性质粒，但谷胱甘肽生物合成缺陷的突变体对磷霉素敏感。耐药但非敏感菌株的提取物能够将谷胱甘肽与1-氯-2,4-二硝基苯结合，证实了酶活性的性质。加合物的形成似乎对谷胱甘肽具有特异性：所测试的其他硫醇（半胱氨酸、N-乙酰半胱氨酸和二硫苏糖醇）均不能修饰磷霉素。
