Frequency of development and associated physiological cost of azithromycin resistance in Chlamydia psittaci 6BC and C-trachomatis L2
Frequency of development and associated physiological cost of azithromycin resistance in Chlamydia psittaci 6BC and C-trachomatis L2
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DOI：
10.1128/aac.00962-07
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发表时间：
2007-12-01
影响因子：
4.9
通讯作者：
Maurelli, Anthony T.
中科院分区：
文献类型：
--
作者：
Binet, Rachel;Maurelli, Anthony T.
阿奇霉素是用于治疗和预防衣原体感染的主要药物。在斑块实验中，以约10-8的频率分离出了裸热衣原体6BC的自发性阿奇霉素耐药突变体。在独特的23S rRNA基因（大肠杆菌编号系统）中具有A(2058)C、A(2059)G或A(2059)C突变的等基因克隆变异体对多种大环内酯类药物（即阿奇霉素、红霉素、乔霉素和螺旋霉素）的mic比亲本菌株高至少100倍，并且对lincosamide克林霉素的耐药性也更高。沙眼衣原体L2变异体在核糖体蛋白L4的第66位（大肠杆菌编号系统）上进行了kin -to- lys替换，使阿奇霉素和红霉素的敏感性降低了8倍，乔霉素和螺旋霉素的敏感性降低了4倍，在亚抑制阿奇霉素浓度下进行了连续传代。在没有选择的情况下，每个突变都能稳定保持，但严重影响衣原体的传染性，这是通过在没有选择的情况下，在纯培养或与等基因亲本1:1竞争的情况下监测每个分离物超过46小时的发育来确定的。本研究的数据支持这样一种假设，即衣原体产生高水平大环内酯类耐药性的机制具有令人望而却步的生理成本，因此可能限制这些重要病原体在体内产生高耐药性克隆。
Azithromycin is a major drug used in the treatment and prophylaxis of chlamydial infections. Spontaneous azithromycin-resistant mutants of Chlamydia psittaci 6BC were isolated in vitro in the plaque assay at a frequency of about 10-8. Isogenic clonal variants with A(2058)C, A(2059)G, or A(2059)C mutations in the unique 23S rRNA gene (Escherichia coli numbering system) displayed MICs for multiple macrolides (i.e., azithromycin, erythromycin, josamycin, and spiramycin) at least 100 times higher than those of the parent strain and were also more resistant to the lincosamide clindamycin. Chlamydia trachomatis L2 variants with a Gin-to-Lys substitution in ribosomal protein L4 at position 66 (E. coli numbering system), conferring an eightfold decrease in azithromycin and erythromycin sensitivities and a fourfold decrease in josamycin and spiramycin sensitivities, were isolated following serial passage in subinhibitory concentrations of azithromycin. Each mutation was stably maintained in the absence of selection but severely affected chlamydial infectivity, as determined by monitoring the development of each isolate over 46 h in the absence of selection, in pure culture or in 1:1 competition with the isogenic parent. Data in this study support the hypothesis that the mechanisms which confer high-level macrolide resistance in chlamydiae carry a prohibitive physiological cost and may thus limit the emergence of highly resistant clones of these important pathogens in vivo.