氨基糖苷
铜绿假单胞菌
乙醛酸循环
柠檬酸循环
三羧酸
妥布霉素
微生物学
抗生素
增强剂
生物
细菌
抗菌剂
生物化学
化学
药理学
新陈代谢
遗传学
作者
Sylvain Meylan,Caroline Porter,Jason H. Yang,Peter Belenky,Arnaud Gutierrez,Michael A. Lobritz,Jihye Park,Sun H. Kim,Samuel M. Moskowitz,James J. Collins
标识
DOI:10.1016/j.chembiol.2016.12.015
摘要
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.
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