Enzyme structural plasticity and the emergence of broad-spectrum antibiotic resistance
Enzyme structural plasticity and the emergence of broad-spectrum antibiotic resistance
复制标题
DOI：
10.1038/embor.2008.9
复制
发表时间：
2008-04-01
期刊：
影响因子：
7.7
通讯作者：
Dardel, Frederic
中科院分区：
文献类型：
--
作者：
Maurice, Frederique;Broutin, Isabelle;Dardel, Frederic
多重耐药致病菌的出现是一个世界性的健康问题。最近，已经鉴定了单一的抗肿瘤修饰乙酰转移酶AAC（6 '）-Ib -氨基糖苷类6'-N-乙酰转移酶的变体-的临床变体，其赋予对大多数氨基糖苷类的延长的抗性，并且更令人惊讶地，赋予对结构上不相关的氟喹诺酮类的延长的抗性。相应的基因由移动的遗传元件携带，并且存在于大多数多重耐药致病菌株中，因此使其对当前疗法构成严重威胁。在这里，我们报告了这种酶的窄谱和广谱抗性变体的晶体结构，这揭示了扩展抗性出现的结构基础。活性位点显示出重要的可塑性，并通过大规模的开口过程适应新的底物。我们还获得了与这两种基板的共晶，并与一个简单的过渡态类似物，这提供了新的线索，设计这种耐药机制的抑制剂。
The emergence of multi-resistant pathogenic bacteria is a worldwide health issue. Recently, clinical variants of a single antibiotic-modifying acetyltransferase, AAC(6')-Ib - a variant of aminoglycoside 6'-N-acetyltransferase - have been identified that confer extended resistance to most aminoglycosides and, more surprisingly, to structurally unrelated fluoroquinolones. The corresponding gene is carried by mobile genetic elements and is present in most multi-resistant pathogenic strains, hence making it a serious threat to current therapies. Here, we report the crystal structures of both narrow- and broad-spectrum resistance variants of this enzyme, which reveal the structural basis for the emergence of extended resistance. The active site shows an important plasticity and has adapted to new substrates by a large-scale gaping process. We have also obtained co-crystals with both substrates, and with a simple transition state analogue, which provides new clues for the design of inhibitors of this resistance mechanism.