Low levels of tetracyclines select for a mutation that prevents the evolution of high-level resistance to tigecycline.

IF 7.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY PLoS Biology Pub Date : 2022-09-28 eCollection Date: 2022-09-01 DOI:10.1371/journal.pbio.3001808
Jennifer Jagdmann, Dan I Andersson, Hervé Nicoloff
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引用次数: 2

Abstract

In a collection of Escherichia coli isolates, we discovered a new mechanism leading to frequent and high-level tigecycline resistance involving tandem gene amplifications of an efflux pump encoded by the tet(A) determinant. Some isolates, despite carrying a functional tet(A), could not evolve high-level tigecycline resistance by amplification due to the presence of a deletion in the TetR(A) repressor. This mutation impaired induction of tetA(A) (encoding the TetA(A) efflux pump) in presence of tetracyclines, with the strongest effect observed for tigecycline, subsequently preventing the development of tet(A) amplification-dependent high-level tigecycline resistance. We found that this mutated tet(A) determinant was common among tet(A)-carrying E. coli isolates and analysed possible explanations for this high frequency. First, while the mutated tet(A) was found in several ST-groups, we found evidence of clonal spread among ST131 isolates, which increases its frequency within E. coli databases. Second, evolution and competition experiments revealed that the mutation in tetR(A) could be positively selected over the wild-type allele at sub-inhibitory concentrations of tetracyclines. Our work demonstrates how low concentrations of tetracyclines, such as those found in contaminated environments, can enrich and select for a mutation that generates an evolutionary dead-end that precludes the evolution towards high-level, clinically relevant tigecycline resistance.

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低水平的四环素选择突变,防止进化为对替加环素的高水平耐药性。
在收集的大肠杆菌分离株中,我们发现了一种导致频繁和高水平的替加环素耐药的新机制,涉及tet(a)决定因子编码的外排泵的串联基因扩增。一些分离株尽管携带功能性tet(a),但由于存在TetR(a)抑制因子缺失,无法通过扩增进化出高水平的替加环素耐药性。该突变破坏了四环素存在时tetA(A)(编码tetA(A)外排泵)的诱导,对替加环素的影响最大,随后阻止了tet(A)扩增依赖的高水平替加环素耐药性的发展。我们发现这种突变的tet(A)决定因素在携带tet(A)的大肠杆菌分离株中很常见,并分析了这种高频率的可能解释。首先,虽然在几个st群中发现了突变的tet(A),但我们发现在ST131分离株中存在克隆传播的证据,这增加了其在大肠杆菌数据库中的频率。其次,进化和竞争实验表明,在四环素的亚抑制浓度下,tetR(A)突变可以正向选择野生型等位基因。我们的工作表明,低浓度的四环素,例如在污染环境中发现的四环素,可以丰富和选择产生进化死胡同的突变,从而阻止进化到高水平,临床相关的替加环素耐药性。
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来源期刊
PLoS Biology
PLoS Biology 生物-生化与分子生物学
CiteScore
14.40
自引率
2.00%
发文量
359
审稿时长
3 months
期刊介绍: PLOS Biology is an open-access, peer-reviewed general biology journal published by PLOS, a nonprofit organization of scientists and physicians dedicated to making the world's scientific and medical literature freely accessible. The journal publishes new articles online weekly, with issues compiled and published monthly. ISSN Numbers: eISSN: 1545-7885 ISSN: 1544-9173
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