Potential of Tetracycline Resistance Proteins To Evolve Tigecycline Resistance.
Potential of Tetracycline Resistance Proteins To Evolve Tigecycline Resistance.
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DOI：
10.1128/aac.02465-15
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发表时间：
2016-02
影响因子：
4.9
通讯作者：
Andersson DI
中科院分区：
文献类型：
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作者：
Linkevicius M;Sandegren L;Andersson DI
替加环素是一种甘氨酰环素抗生素，对多重耐药细菌病原体具有活性。本研究的目的是检测泰特（A）、泰特（K）、泰特（M）和泰特（X）四环素耐药蛋白获得导致替加环素耐药突变的潜力，并确定这如何影响对早期四环素类药物的耐药性。所有四种tet基因的突变导致大肠杆菌中替加环素MIC显著增加，表达突变体泰特（A）和泰特（X）变体的菌株达到临床相关MIC（分别为2 mg/L和3 mg/L）。突变主要积累在外排泵的跨膜结构域中，最有可能增加替加环素作为底物的适应性。所有选择的泰特（M）突变体在结构域IV的功能上最重要的环III中含有至少一个突变。在泰特（M）突变体中，该环亮氨酸505的缺失导致替加环素MIC（0.5 mg/L）的最高增加。它还引起对早期四环素类药物的附带敏感性。大多数泰特（X）突变体显示出对所有三类四环素的活性增加。所有测试的泰特蛋白都有可能获得突变，导致替加环素MIC增加。由于tet基因广泛存在于致病菌中，并且易于通过水平基因转移传播，因此通过改变现有泰特蛋白而产生的耐药性可能会危及替加环素的未来医疗用途。我们预测，泰特（X）可能成为未来最有问题的泰特决定因素，因为其微弱的内在替加环素活性可以通过突变提高到临床相关水平，而不会因其他四环素而损失活性。
Tigecycline is a glycylcycline antibiotic active against multidrug-resistant bacterial pathogens. The objectives of our study were to examine the potential of the Tet(A), Tet(K), Tet(M), and Tet(X) tetracycline resistance proteins to acquire mutations causing tigecycline resistance and to determine how this affects resistance to earlier classes of tetracyclines. Mutations in all four tet genes caused a significant increase in the tigecycline MIC in Escherichia coli, and strains expressing mutant Tet(A) and Tet(X) variants reached clinically relevant MICs (2 mg/liter and 3 mg/liter, respectively). Mutations predominantly accumulated in transmembrane domains of the efflux pumps, most likely increasing the accommodation of tigecycline as a substrate. All selected Tet(M) mutants contained at least one mutation in the functionally most important loop III of domain IV. Deletion of leucine 505 of this loop led to the highest increase of the tigecycline MIC (0.5 mg/liter) among Tet(M) mutants. It also caused collateral sensitivity to earlier classes of tetracyclines. A majority of the Tet(X) mutants showed increased activity against all three classes of tetracylines. All tested Tet proteins have the potential to acquire mutations leading to increased MICs of tigecycline. As tet genes are widely found in pathogenic bacteria and spread easily by horizontal gene transfer, resistance development by alteration of existing Tet proteins might compromise the future medical use of tigecycline. We predict that Tet(X) might become the most problematic future Tet determinant, since its weak intrinsic tigecycline activity can be mutationally improved to reach clinically relevant levels without collateral loss in activity to other tetracyclines.