Importance of Core Genome Functions for an Extreme Antibiotic Resistance Trait.
Importance of Core Genome Functions for an Extreme Antibiotic Resistance Trait.
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DOI：
10.1128/mbio.01655-17
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发表时间：
2017-12-12
期刊：
影响因子：
6.4
通讯作者：
Manoil C
中科院分区：
文献类型：
--
作者：
Gallagher LA;Lee SA;Manoil C
细菌的极端抗生素耐药性与强大的失活酶的表达和辅助基因组元件中编码的其他功能有关。核心基因组过程对此类细菌高水平耐药性的贡献尚不清楚。在这里报告的工作中，我们评估了核心和辅助功能的相对重要性，高水平的耐药性的氨基糖苷类妥布霉素在医院病原体鲍曼不动杆菌。有三条证据表明，在这种抵抗中，核心功能占据了首要地位。首先，在一个基因组规模的突变分析，使用转座子测序和验证594个单独的突变体，几乎所有的突变减少妥布霉素耐药失活的核心基因，一些具有更强的表型比消除氨基糖苷类失活酶所造成的。第二，介导抗性的核心功能在野生型和缺失突变体中几乎相同，缺失突变体缺乏编码失活酶的基因组抗性岛。因此，大多数或所有的核心抗性决定因素，重要的酶的情况下，也是重要的酶的存在。第三，不同的核心突变引起的妥布霉素耐药性的减少是加性的，可以构建保留辅助耐药基因的高度敏感的双重和三重突变体（MIC降低250倍）。对内源性妥布霉素耐药性贡献最大的核心过程包括磷脂生物合成、磷酸盐调节和包膜稳态。细菌抗生素耐药性的不可阻挡的增加威胁着破坏上世纪改变医学的许多程序。应对抗生素耐药性挑战的一个策略是开发破坏耐药性的药物。为了确定这些佐剂的潜在靶点，我们确定了已知最高耐药性病原体之一对一类重要抗生素的耐药性的潜在功能。
Extreme antibiotic resistance in bacteria is associated with the expression of powerful inactivating enzymes and other functions encoded in accessory genomic elements. The contribution of core genome processes to high-level resistance in such bacteria has been unclear. In the work reported here, we evaluated the relative importance of core and accessory functions for high-level resistance to the aminoglycoside tobramycin in the nosocomial pathogen Acinetobacter baumannii. Three lines of evidence establish the primacy of core functions in this resistance. First, in a genome scale mutant analysis using transposon sequencing and validation with 594 individual mutants, nearly all mutations reducing tobramycin resistance inactivated core genes, some with stronger phenotypes than those caused by the elimination of aminoglycoside-inactivating enzymes. Second, the core functions mediating resistance were nearly identical in the wild type and a deletion mutant lacking a genome resistance island that encodes the inactivating enzymes. Thus, most or all of the core resistance determinants important in the absence of the enzymes are also important in their presence. Third, reductions in tobramycin resistance caused by different core mutations were additive, and highly sensitive double and triple mutants (with 250-fold reductions in the MIC) that retained accessory resistance genes could be constructed. Core processes that contribute most strongly to intrinsic tobramycin resistance include phospholipid biosynthesis, phosphate regulation, and envelope homeostasis. The inexorable increase in bacterial antibiotic resistance threatens to undermine many of the procedures that transformed medicine in the last century. One strategy to meet the challenge antibiotic resistance poses is the development of drugs that undermine resistance. To identify potential targets for such adjuvants, we identified the functions underlying resistance to an important class of antibiotics for one of the most highly resistant pathogens known.