摘要

微生物在到达细菌细胞前克服不同种类抗生素的潜力很大程度上尚未被探索。在这里，我们表明，暴露于亚致死浓度抗生素浓度时，由伯克霍尔德氏菌产生的可溶性细菌脂质运载蛋白在体外和体内增加对各种抗生素的抗性。这些表型通过来自铜绿假单胞菌，结核分枝杆菌和耐甲氧西林金黄色葡萄球菌的脂质运载蛋白基因的B.centocepacia中的异源表达而被重述。纯化的脂质运载蛋白结合不同种类的杀菌抗生素并促成体内细菌存活。实验和X射线晶体结构指导的计算研究表明脂质运载蛋白通过在细胞外空间捕获抗生素来抵抗抗生素作用。我们还证明脂溶性维生素通过以比抗生素更高的亲和力结合细菌脂质运载蛋白来防止抗生素捕获。因此，细菌脂质运载蛋白通过在感染部位的细胞外空间中捕获多种抗生素而导致抗微生物耐药性，这可以被已知的维生素抵消。

The potential for microbes to overcome antibiotics of different classes before they reach bacterial cells is largely unexplored. Here we show that a soluble bacterial lipocalin produced by Burkholderia cenocepacia upon exposure to sublethal antibiotic concentrations increases resistance to diverse antibiotics in vitro and in vivo. These phenotypes were recapitulated by heterologous expression inB. cenocepacia of lipocalin genes from Pseudomonas aeruginosa, Mycobacterium tuberculosis, and methicillin-resistant Staphylococcus aureus. Purified lipocalin bound different classes of bactericidal antibiotics and contributed to bacterial survival in vivo. Experimental and X-ray crystal structure-guided computational studies revealed that lipocalins counteract antibiotic action by capturing antibiotics in the extracellular space. We also demonstrated that fat-soluble vitamins prevent antibiotic capture by binding bacterial lipocalin with higher affinity than antibiotics. Therefore, bacterial lipocalins contribute to antimicrobial resistance by capturing diverse antibiotics in the extracellular space at the site of infection, which can be counteracted by known vitamins.

http://mbio.asm.org/content/8/2/e00225-17.short