Inhibition of protein synthesis by streptogramins and related antibiotics
Inhibition of protein synthesis by streptogramins and related antibiotics
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DOI：
10.1093/jac/39.suppl_1.7
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发表时间：
1997-05-01
影响因子：
5.2
通讯作者：
Vannuffel, P
中科院分区：
文献类型：
--
作者：
Cocito, C;DiGiambattista, M;Vannuffel, P
链状gramin和相关抗生素（lincoamide和大环内酯类）（MLS）是细菌蛋白质合成的重要抑制剂。这一过程的关键反应是在连接50S核糖体p位点的生长肽链（肽基trna）和连接a位点的氨基酰基trna之间形成肽键。该反应由50S核糖体的肽基转移酶催化中心催化。特别是A型和B型链状gramin已被证明通过抑制底物附着于A和P位点以及抑制肽链延伸来阻断该反应。A型和B型组分之间的协同作用是由于A型化合物对肽基转移酶中心施加的构象变化以及对蛋白质合成的早期和晚期的抑制。构象变化增加了核糖体对B型链状蛋白的亲和力。微生物对MLSB抗生素的耐药性主要是由于rRNA碱基的突变，在肽基转移酶中心产生构象变化。这可能导致对单一抑制剂或一组抗生素（MLSB）产生耐药性。A型链状gramin的活性得以保留，从而解释了联合链状gramin对大环内酯和林肯胺耐药菌株的抑制作用的改善。然而，由于a型和B型化合物的协同作用，对链状gramin的耐药性的发展可能不是一个问题，这在对MLSB耐药的菌株中也得到了证明，即只有当a型链状gramin耐药决定因素与B型链状gramin耐药决定因素同时存在时，才有可能对联合链状gramin产生高水平的耐药性。
The streptogramins and related antibiotics (the lincosamides and macrolides) (MLS) are important inhibitors of bacterial protein synthesis. The key reaction in this process is the formation of a peptide bond between the growing peptide chain (peptidyl-tRNA) linked to the P-site of the 50S ribosome and aminoacyl-tRNA linked to the A site. This reaction is catalysed by the peptidyl transferase catalytic centre of the 50S ribosome. Type A and B streptogramins in particular have been shown to block this reaction through the inhibition of substrate attachment to the A and P sites and inhibition of peptide chain elongation. Synergy between type A and B components results from conformational changes imposed upon the peptidyl transferase centre by type A compounds and by inhibition of both early and late stages of protein synthesis. The conformational change increases ribosomal affinity for type B streptogramins. Microbial resistance to the MLSB antibiotics is largely attributable to mutations of rRNA bases, producing conformational changes in the peptidyl transferase centre. This can result in resistance to a single inhibitor or to a group of antibiotics (MLSB). The activity of type A streptogramin is retained thus explaining the improved inhibitory action of the combined streptogramins against macrolide and lincosamide-resistant strains. However, the development of resistance to the streptogramins may be less of a problem because of the synergic effect of type A and B compounds which has also been demonstrated in strains resistant to MLSB i.e., high level resistance to the combined streptogramins is only likely when type A streptogramin resistance determinants are present along with type B streptogramin resistance determinants.