BINDING OF NOVEL MACROLIDE STRUCTURES TO MACROLIDES-LINCOSAMIDES-STREPTOGRAMIN B-RESISTANT RIBOSOMES INHIBITS PROTEIN-SYNTHESIS AND BACTERIAL-GROWTH
BINDING OF NOVEL MACROLIDE STRUCTURES TO MACROLIDES-LINCOSAMIDES-STREPTOGRAMIN B-RESISTANT RIBOSOMES INHIBITS PROTEIN-SYNTHESIS AND BACTERIAL-GROWTH
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DOI：
10.1128/aac.33.7.1058
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发表时间：
1989-07-01
影响因子：
4.9
通讯作者：
KADAM, SK
中科院分区：
文献类型：
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作者：
GOLDMAN, RC;KADAM, SK
23S rRNA中腺嘌呤2058的二甲基化使细菌对大环内酯类、林肯胺类和链状gramin B具有耐药性（MLS耐药性），因为改变后的50S核糖体亚基上的抗生素结合位点不再可达。我们现在报道红霉素的某些6- o -甲基-11,12-环氨基甲酸酯衍生物能够结合二甲基化的mls抗性50S核糖体亚基，从而抑制蛋白质合成和细胞生长。其中一种新结构，11-脱氧-11-（羧基氨基）-6- o -甲基红霉素A 11,12-（环酯）衍生物，结构1a，进行了详细的研究。对枯草芽孢杆菌敏感和耐药提取物均有50%的抑制作用，抑制浓度分别为0.4和20 .mu。M,分别。该衍生物特异性结合枯草芽孢杆菌和金黄色葡萄球菌制备的mls耐药核糖体的50S亚基上的单个位点，未观察到与30S亚基的结合。衍生物1a与敏感核糖体和耐药核糖体的关联速率常数分别比亲本化合物红霉素与敏感核糖体的关联速率常数慢100倍和500倍。从敏感和耐药核糖体中分离红霉素的速率常数比从敏感核糖体中分离红霉素的速率慢50- 100倍。此外，1a与敏感的50S亚基结合可诱导ermC和ermD，而与耐药的50S亚基结合则不会，这表明1a对敏感和耐药50S亚基功能的扰动是不同的。这些数据表明，1a与mls抗性核糖体的相互作用是独特的，这种相互作用导致核糖体功能的新变构扰动。
Dimethylation of adenine 2058 in 23S rRNA renders bacteria resistant to macrolides, lincosamides, and streptogramin B (MLS resistance), because the antibiotic binding site on the altered 50S ribosomal subunit is no longer accessible. We now report that certain 6-O-methyl-11,12-cyclic carbamate derivatives of erythromycin are able to bind to dimethylated MLS-resistant 50S ribosomal subunits, thus inhibiting protein synthesis and cell growth. One of these novel structures, an 11-deoxy-11-(carboxyamino)-6-O-methylerythromycin A 11,12-(cyclic ester) derivative, structure 1a, was studied in detail. It inhibited in vitro protein synthesis in extracts prepared from both susceptible and MLS-resistant Bacillus subtilis with 50% inhibitory concentrations of 0.4 and 20 .mu.M, respectively. The derivative bound specifically to a single site on the 50S subunit of MLS-resistant ribosomes prepared from B. subtilis and Staphylococcus aureus, and no binding to 30S subunits was observed. The association rate constant of derivative 1a with sensitive and resistant ribosomes was 100- and 500-fold slower, respectively, than that of the parent compound, erythromycin, with sensitive ribosomes. The dissociation rate constant of 1a from sensitive and resistant ribosomes was 50- to 100-fold slower than the rated of erythromycin dissociation from sensitive ribosomes. Furthermore, 1a binding to sensitive 50S subunits led to induction of ermC and ermD, while binding to resistant 50S subunits did not, showing that perturbation of sensitive and resistant 50S subunit function by 1a differs. These data demonstrated that 1a is unique in its interaction with MLS-resistant ribosomes and that this interaction causes a novel allosteric perturbation of ribosome function.