Carbon Sources Tune Antibiotic Susceptibility in Pseudomonas aeruginosa via Tricarboxylic Acid Cycle Control.
Carbon Sources Tune Antibiotic Susceptibility in Pseudomonas aeruginosa via Tricarboxylic Acid Cycle Control.
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DOI：
10.1016/j.chembiol.2016.12.015
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发表时间：
2017-02-16
影响因子：
8.6
通讯作者：
Collins JJ
中科院分区：
文献类型：
--
作者：
Meylan S;Porter CBM;Yang JH;Belenky P;Gutierrez A;Lobritz MA;Park J;Kim SH;Moskowitz SM;Collins JJ
代谢休眠细菌对有效的抗微生物治疗提出了关键挑战，因为这些细菌在遗传上对抗生素治疗敏感，但在表型上耐受。这种耐受性归因于药物摄取受损，这可以通过代谢刺激逆转。在这里，我们评估的影响，中央碳代谢物刺激氨基糖苷类抗生素的敏感性，在病原体铜绿假单胞菌。我们确定富马酸作为妥布霉素增效剂，激活细胞呼吸，并通过刺激三羧酸（TCA）循环产生质子动力。与此相反，我们发现，乙醛酸诱导表型耐受抑制细胞呼吸与乙酰辅酶A分流通过乙醛酸分流，尽管药物进口。总的来说，这项工作表明，TCA循环活性是重要的氨基糖苷类摄取和下游致死性，并确定了一个潜在的策略，加强氨基糖苷类治疗铜绿假单胞菌感染。
Metabolically dormant bacteria present a critical challenge to effective antimicrobial therapy because these bacteria are genetically susceptible to antibiotic treatment but phenotypically tolerant. Such tolerance has been attributed to impaired drug uptake, which can be reversed by metabolic stimulation. Here, we evaluate the effects of central carbon metabolite stimulations on aminoglycoside sensitivity in the pathogen Pseudomonas aeruginosa. We identify fumarate as a tobramycin potentiator that activates cellular respiration and generates a proton motive force by stimulating the tricarboxylic acid (TCA) cycle. In contrast, we find that glyoxylate induces phenotypic tolerance by inhibiting cellular respiration with acetyl-coenzyme A diversion through the glyoxylate shunt, despite drug import. Collectively, this work demonstrates that TCA cycle activity is important for both aminoglycoside uptake and downstream lethality and identifies a potential strategy for potentiating aminoglycoside treatment of P. aeruginosa infections.