Resistance to Macrolide Antibiotics in Public Health Pathogens
Resistance to Macrolide Antibiotics in Public Health Pathogens
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DOI：
10.1101/cshperspect.a025395
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发表时间：
2016-10-01
影响因子：
5.4
通讯作者：
Sutcliffe, Joyce
中科院分区：
文献类型：
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作者：
Fyfe, Corey;Grossman, Trudy H.;Sutcliffe, Joyce
大环内酯类耐药机制可以是基于靶点的，23 S核糖体RNA（rRNA）残基的变化或核糖体蛋白L4或L22的突变影响核糖体与抗生素的相互作用。或者，通过获得性rRNA甲基转移酶（ermo（红霉素核糖体甲基化）基因的产物）对23 S rRNA结构域V中的A2058进行单甲基化或二甲基化，可以干扰抗生素结合。获得的编码外排泵的基因，在肺炎球菌/链球菌中最主要是mef（A）+ msr（D），在葡萄球菌中最主要是msr（A/B），也介导耐药性。药物失活机制包括磷酸转移酶对C5位氨基糖的20-羟基的磷酸化和酯酶对大环内酯的水解。这些获得的基因受到翻译或转录衰减的调节，主要是因为当这些基因，特别是rRNA甲基转移酶，被高度诱导或组成型表达时，细胞不太适合。基因表达的诱导与大环内酯类的作用机制巧妙地联系在一起，依赖于在新生多肽的特定序列处停滞的与磷脂结合的核糖体来促进下游序列的转录或翻译。
Macrolide resistance mechanisms can be target-based with a change in a 23S ribosomal RNA (rRNA) residue or a mutation in ribosomal protein L4 or L22 affecting the ribosome's interaction with the antibiotic. Alternatively, mono-or dimethylation of A2058 in domain V of the 23S rRNA by an acquired rRNA methyltransferase, the product of an erm (erythromycin ribosome methylation) gene, can interfere with antibiotic binding. Acquired genes encoding efflux pumps, most predominantly mef(A) + msr(D) in pneumococci/streptococci and msr(A/B) in staphylococci, also mediate resistance. Drug-inactivating mechanisms include phosphorylation of the 20-hydroxyl of the amino sugar found at position C5 by phosphotransferases and hydrolysis of the macrocyclic lactone by esterases. These acquired genes are regulated by either translation or transcription attenuation, largely because cells are less fit when these genes, especially the rRNA methyltransferases, are highly induced or constitutively expressed. The induction of gene expression is cleverly tied to the mechanism of action of macrolides, relying on antibiotic-bound ribosomes stalled at specific sequences of nascent polypeptides to promote transcription or translation of downstream sequences.