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首页> 外文期刊>Journal of bacteriology >A Screen for Antibiotic Resistance Determinants Reveals a Fitness Cost of the Flagellum in Pseudomonas aeruginosa
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A Screen for Antibiotic Resistance Determinants Reveals a Fitness Cost of the Flagellum in Pseudomonas aeruginosa

机译：抗生素抗性决定簇的筛网揭示了铜绿假单胞菌的鞭毛的健身成本

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The intrinsic resistance of Pseudomonas aeruginosa to many antibiotics limits treatment options for pseudomonal infections. P. aeruginosa’s outer membrane is highly impermeable and decreases antibiotic entry into the cell. We used an unbiased high-throughput approach to examine mechanisms underlying outer membrane-mediated antibiotic exclusion. Insertion sequencing (INSeq) identified genes that altered fitness in the presence of linezolid, rifampin, and vancomycin, antibiotics to which P. aeruginosa is intrinsically resistant. We reasoned that resistance to at least one of these antibiotics would depend on outer membrane barrier function, as previously demonstrated in Escherichia coli and Vibrio cholerae. This approach demonstrated a critical role of the outer membrane barrier in vancomycin fitness, while efflux pumps were primary contributors to fitness in the presence of linezolid and rifampin. Disruption of flagellar assembly or function was sufficient to confer a fitness advantage to bacteria exposed to vancomycin. These findings clearly show that loss of flagellar function alone can confer a fitness advantage in the presence of an antibiotic. IMPORTANCE The cell envelopes of Gram-negative bacteria render them intrinsically resistant to many classes of antibiotics. We used insertion sequencing to identify genes whose disruption altered the fitness of a highly antibiotic-resistant pathogen, Pseudomonas aeruginosa, in the presence of antibiotics usually excluded by the cell envelope. This screen identified gene products involved in outer membrane biogenesis and homeostasis, respiration, and efflux as important contributors to fitness. An unanticipated fitness cost of flagellar assembly and function in the presence of the glycopeptide antibiotic vancomycin was further characterized. These findings have clinical relevance for individuals with cystic fibrosis who are infected with P. aeruginosa and undergo treatment with vancomycin for a concurrent Staphylococcus aureus infection.
机译：铜绿假单胞菌对许多抗生素的固有抗性限制了假型感染的治疗方案。 P.铜绿假单胞菌的外膜是高度渗透性的并且将抗生素进入细胞中。我们使用了一个无偏见的高通量方法来检查外膜介导的抗生素排除型下面的机制。插入测序（Inseq）鉴定的基因在Linezolid，利福平和万古霉素存在下改变适应性，P.铜绿假单胞菌的抗生素是本质上抗性的。我们推断对这些抗生素中的至少一种的抵抗力取决于外膜屏障功能，如前所述，如先前在大肠杆菌和霍乱霍乱。这种方法证明了外膜屏障在万古霉素健身中的关键作用，而流水泵是在Linezolid和利福平存在下的适应性的主要贡献者。鞭毛组装或函数的破坏足以赋予暴露于万古霉素的细菌的健康优势。这些发现清楚地表明，单独鞭打功能的损失可以在抗生素存在下赋予健康优势。重要性革兰氏阴性细菌的细胞包膜使它们本质上抵抗许多抗生素。我们使用插入测序来鉴定破坏改变高抗生素抗性病原体的适应性，铜绿假单胞菌在通常被由细胞包膜中排除的抗生素存在的基因。该筛选鉴定了涉及外膜生物发生和稳态，呼吸和流出的基因产物作为适应性的重要贡献者。进一步表征了在存在糖肽抗生素万古霉素存在下的鞭毛组装和功能的意外成本。这些发现对具有囊性纤维化的个体具有囊性纤维化的临床相关性，该纤维化是用P.铜绿假单胞菌感染的，并用万古霉素进行治疗，用于同时的金黄色葡萄球菌感染。

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