Clinically relevant mutant DNA gyrase alters supercoiling, changes the transcriptome, and confers multidrug resistance.
Clinically relevant mutant DNA gyrase alters supercoiling, changes the transcriptome, and confers multidrug resistance.
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临床相关的突变体DNA回旋酶改变了超螺旋，改变了转录组，并赋予多药电阻。
DOI：
10.1128/mbio.00273-13
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发表时间：
2013-07-23
期刊：
影响因子：
6.4
通讯作者：
Piddock LJ
中科院分区：
文献类型：
--
作者：
Webber MA;Ricci V;Whitehead R;Patel M;Fookes M;Ivens A;Piddock LJ
细菌DNA在拓扑异构酶的作用下保持超卷曲状态。超卷曲的改变影响包括转录在内的基本细胞过程。本研究表明，沙门氏菌GyrA第87位的取代会影响其对抗生素（包括非喹诺酮类药物）的敏感性，改变全局超螺旋，并导致转录组改变，增加应激反应途径的表达。GyrA Asp87Gly突变体对多种抗生素的敏感性降低并非外排活性增加或活性氧产生减少的结果。这些数据表明，GyrA中经常观察到的和临床相关的替换导致许多基因的表达改变，包括那些在逆境中细菌生存的重要基因，这表明GyrA突变体在特定条件下可能具有选择优势。我们的发现有助于解释致病性菌株对喹诺酮类药物的高耐药率，并可能部分解释为什么这些突变菌株在进化上是成功的。氟喹诺酮类药物是一种强大的抗生素，其作用目标是帮助细菌维持染色体构象的细菌酶。靶酶的突变使细菌对这些抗生素产生耐药性，氟喹诺酮类药物耐药性很常见。我们在这里表明，这些突变还通过触发细胞内的防御性应激反应，提供针对多种其他抗菌剂的保护。这项工作表明，氟喹诺酮耐药性突变可能在一系列条件下是有益的。
Bacterial DNA is maintained in a supercoiled state controlled by the action of topoisomerases. Alterations in supercoiling affect fundamental cellular processes, including transcription. Here, we show that substitution at position 87 of GyrA of Salmonella influences sensitivity to antibiotics, including nonquinolone drugs, alters global supercoiling, and results in an altered transcriptome with increased expression of stress response pathways. Decreased susceptibility to multiple antibiotics seen with a GyrA Asp87Gly mutant was not a result of increased efflux activity or reduced reactive-oxygen production. These data show that a frequently observed and clinically relevant substitution within GyrA results in altered expression of numerous genes, including those important in bacterial survival of stress, suggesting that GyrA mutants may have a selective advantage under specific conditions. Our findings help contextualize the high rate of quinolone resistance in pathogenic strains of bacteria and may partly explain why such mutant strains are evolutionarily successful. Fluoroquinolones are a powerful group of antibiotics that target bacterial enzymes involved in helping bacteria maintain the conformation of their chromosome. Mutations in the target enzymes allow bacteria to become resistant to these antibiotics, and fluoroquinolone resistance is common. We show here that these mutations also provide protection against a broad range of other antimicrobials by triggering a defensive stress response in the cell. This work suggests that fluoroquinolone resistance mutations may be beneficial under a range of conditions.