Arthur M, Brisson-Noël A, Courvalin P
Unité des Agents Antibactériens, Centre National de la Recherche Scientifique U.A. 271, Institut Pasteur, Paris, France.
J Antimicrob Chemother. 1987 Dec;20(6):783-802. doi: 10.1093/jac/20.6.783.
Resistance to macrolide, lincosamide and streptogramin antibiotics is due to alteration of the target site or detoxification of the antibiotic. Postranscriptional methylation of 23S ribosomal rRNA confers resistance to macrolide (M), lincosamide (L) and streptogramin (S) B-type antibiotics, the so-called MLSB phenotype. Several classes of rRNA methylases conferring resistance to MLSB antibiotics have been characterized in Gram-positive cocci, in Bacillus spp, and in strains of actinomycetes producing erythromycin. The enzymes catalyze N6-dimethylation of an adenine residue situated in a highly conserved region of prokaryotic 23S rRNA. In this review, we compare the amino acid sequences of the rRNA methylases and analyze the codon usage in the corresponding erm (erythromycin resistance methylase) genes. The homology detected at the protein level is consistent with the notion that an ancestor of the erm genes was implicated in erythromycin resistance in a producing strain. However, the rRNA methylases of producers and non-producers present substantial sequence diversity. In Gram-positive bacteria the preferential codon usage in the erm genes reflects the guanosine plus cytosine content of the chromosome of the host. These observations suggest that the presence of erm genes in these micro-organisms is ancient. By contrast, it would appear that enterobacteria have acquired only recently an rRNA methylase gene of the ermB class from a Gram-positive coccus since the genes isolated in Escherichia coli and in Gram-positive cocci are highly homologous (homology greater than 98%) and present a codon usage typical of the latter micro-organisms. As opposed to the MLSB phenotype which results from a single biochemical mechanism, inactivation of structurally related antibiotics of the MLS group involves synthesis of various other enzymes. In enterobacteria, resistance to erythromycin and oleandomycin is due to production of erythromycin esterases which hydrolyze the lactone ring of the 14-membered macrolides. We recently reported the nucleotide sequence of ereA and ereB (erythromycin resistance esterase) genes which encode erythromycin esterases type I and II, respectively. The amino acid sequences of the two isozymes do not exhibit statistically significant homology. Analysis of codon usage in both genes suggests that esterase type I is indigenous to E. coli, whereas the type II enzyme was acquired by E. coli from a phylogenetically remote micro-organism. Inactivation of lincosamides, first reported in staphylococci and lactobacilli of animal origin, was also recently detected in Gram-positive cocci isolated from humans.(ABSTRACT TRUNCATED AT 400 WORDS)
对大环内酯类、林可酰胺类和链阳菌素类抗生素的耐药性是由于靶位点的改变或抗生素的解毒作用。23S核糖体rRNA的转录后甲基化赋予了对大环内酯类（M）、林可酰胺类（L）和链阳菌素B型（S）抗生素的耐药性，即所谓的MLSB表型。在革兰氏阳性球菌、芽孢杆菌属以及产生红霉素的放线菌菌株中，已鉴定出几类赋予对MLSB抗生素耐药性的rRNA甲基化酶。这些酶催化位于原核生物23S rRNA高度保守区域的一个腺嘌呤残基的N6-二甲基化。在本综述中，我们比较了rRNA甲基化酶的氨基酸序列，并分析了相应erm（红霉素耐药甲基化酶）基因的密码子使用情况。在蛋白质水平检测到的同源性与erm基因的一个祖先参与产生菌株中红霉素耐药性的观点一致。然而，产生菌和非产生菌的rRNA甲基化酶存在大量的序列差异。在革兰氏阳性细菌中，erm基因中优先使用的密码子反映了宿主染色体中鸟嘌呤加胞嘧啶的含量。这些观察结果表明这些微生物中erm基因的存在由来已久。相比之下，肠杆菌似乎是最近才从革兰氏阳性球菌获得了ermB类的rRNA甲基化酶基因，因为在大肠杆菌和革兰氏阳性球菌中分离到的基因高度同源（同源性大于98%），并且呈现出后者典型的密码子使用情况。与由单一生化机制导致的MLSB表型不同，MLS组结构相关抗生素的失活涉及多种其他酶的合成。在肠杆菌中，对红霉素和竹桃霉素的耐药性是由于产生了红霉素酯酶，该酶可水解14元大环内酯类的内酯环。我们最近报道了ereA和ereB（红霉素耐药酯酶）基因的核苷酸序列，它们分别编码I型和II型红霉素酯酶。这两种同工酶的氨基酸序列没有显示出统计学上的显著同源性。对这两个基因密码子使用情况的分析表明，I型酯酶是大肠杆菌固有的，而II型酶是大肠杆菌从一个系统发育关系较远的微生物获得的。林可酰胺类的失活最早在动物源葡萄球菌和乳酸杆菌中报道，最近在从人类分离的革兰氏阳性球菌中也被检测到。（摘要截于400字）
