Thorsing Mette, Bentin Thomas, Givskov Michael, Tolker-Nielsen Tim, Goltermann Lise
Costerton Biofilm Center, Department of Immunology and Microbiology, University of Copenhagen, Blegdamsvej 3b, 2200 Copenhagen, Denmark.
Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3b, 2200 Copenhagen, Denmark.
Microbiology (Reading). 2015 Oct;161(10):1999-2007. doi: 10.1099/mic.0.000152. Epub 2015 Aug 4.
Here, the influence of metabolizable sugars on the susceptibility of Escherichia coli to β-lactam antibiotics was investigated. Notably, monitoring growth and survival of mono- and combination-treated planktonic cultures showed a 1000- to 10 000-fold higher antibacterial efficacy of carbenicillin and cefuroxime in the presence of certain sugars, whereas other metabolites had no effect on β-lactam sensitivity. This effect was unrelated to changes in growth rate. Light microscopy and flow cytometry profiling revealed that bacterial filaments, formed due to β-lactam-mediated inhibition of cell division, rapidly appeared upon β-lactam mono-treatment and remained stable for up to 18 h. The presence of metabolizable sugars in the medium did not change the rate of filamentation, but led to lysis of the filaments within a few hours. No lysis occurred in E. coli mutants unable to metabolize the sugars, thus establishing sugar metabolism as an important factor influencing the bactericidal outcome of β-lactam treatment. Interestingly, the effect of sugar on β-lactam susceptibility was suppressed in a strain unable to synthesize the nutrient stress alarmone (p)ppGpp. Here, to the best of our knowledge, we demonstrate for the first time a specific and significant increase in β-lactam sensitivity due to sugar metabolism in planktonic, exponentially growing bacteria, unrelated to general nutrient availability or growth rate. Understanding the mechanisms underlying the nutritional influences on antibiotic sensitivity is likely to reveal new proteins or pathways that can be targeted by novel compounds, adding to the list of pharmacodynamic adjuvants that increase the efficiency and lifespan of conventional antibiotics.
在此，研究了可代谢糖对大肠杆菌对β-内酰胺类抗生素敏感性的影响。值得注意的是，对单药处理和联合处理的浮游培养物的生长和存活情况进行监测发现，在某些糖存在的情况下，羧苄青霉素和头孢呋辛的抗菌效力提高了1000至10000倍，而其他代谢物对β-内酰胺敏感性没有影响。这种效应与生长速率的变化无关。光学显微镜和流式细胞术分析显示，由于β-内酰胺介导的细胞分裂抑制而形成的细菌丝状物在β-内酰胺单药处理后迅速出现，并在长达18小时内保持稳定。培养基中可代谢糖的存在并没有改变丝状化的速率，但导致丝状物在数小时内溶解。在无法代谢这些糖的大肠杆菌突变体中没有发生溶解，从而确定糖代谢是影响β-内酰胺治疗杀菌效果的一个重要因素。有趣的是，在无法合成营养应激警报素（p）ppGpp的菌株中，糖对β-内酰胺敏感性的影响受到抑制。在此，据我们所知，我们首次证明在浮游的、指数生长的细菌中，由于糖代谢导致β-内酰胺敏感性有特异性且显著的增加，这与一般营养可利用性或生长速率无关。了解营养对抗生素敏感性影响的潜在机制可能会揭示新的蛋白质或途径，这些可被新型化合物靶向，从而增加能够提高传统抗生素效率和使用寿命的药效学佐剂的种类。
