Department of Bacteriology, Capital Institute of Pediatrics, Beijing, China.
School of Pharmaceutical Sciences, Jilin University, Changchun, China.
Microbiol Spectr. 2023 Aug 17;11(4):e0003123. doi: 10.1128/spectrum.00031-23. Epub 2023 Jun 20.
High-alcohol-producing K. pneumoniae (HiAlc ) causes nonalcoholic fatty liver disease (NAFLD) by producing excess endogenous alcohol in the gut of patients with NAFLD, using glucose as the main carbon source. The role of glucose in the response of HiAlc to environmental stresses such as antibiotics remains unclear. In this study, we found that glucose could enhance the resistance of HiAlc to polymyxins. First, glucose inhibited the expression of in HiAlc and promoted the increase of capsular polysaccharide (CPS), which promoted the drug resistance of HiAlc . Second, glucose maintained high ATP levels in HiAlc cells under the pressure of polymyxins, enhancing the resistance of the cells to the killing effect of antibiotics. Notably, the inhibition of CPS formation and the decrease of intracellular ATP levels could both effectively reverse glucose-induced polymyxins resistance. Our work demonstrated the mechanism by which glucose induces polymyxins resistance in HiAlc , thereby laying the foundation for developing effective treatments for NAFLD caused by HiAlc . HiAlc can use glucose to produce excess endogenous alcohol for promoting the development of NAFLD. Polymyxins are the last line of antibiotics and are commonly used to treat infections caused by carbapenem-resistant K. pneumoniae. In this study, we found that glucose increased bacterial resistance to polymyxins via increasing CPS and maintaining intracellular ATP; this increases the risk of failure to treat NAFLD caused by multidrug-resistant HiAlc infection. Further research revealed the important roles of glucose and the global regulator, CRP, in bacterial resistance and found that inhibiting CPS formation and decreasing intracellular ATP levels could effectively reverse glucose-induced polymyxins resistance. Our work reveals that glucose and the regulatory factor CRP can affect the resistance of bacteria to polymyxins, laying a foundation for the treatment of infections caused by multidrug-resistant bacteria.
高产酒精的肺炎克雷伯菌（HiAlc）通过在非酒精性脂肪性肝病（NAFLD）患者的肠道中产生过量的内源性酒精，利用葡萄糖作为主要碳源，导致 NAFLD。葡萄糖在 HiAlc 对环境应激（如抗生素）的反应中的作用尚不清楚。在这项研究中，我们发现葡萄糖可以增强 HiAlc 对多黏菌素的耐药性。首先，葡萄糖抑制了 HiAlc 中基因的表达，并促进了荚膜多糖（CPS）的增加，从而提高了 HiAlc 的耐药性。其次，葡萄糖在多黏菌素的压力下维持了 HiAlc 细胞内的高 ATP 水平，增强了细胞对抗生素杀伤作用的耐药性。值得注意的是，抑制 CPS 形成和降低细胞内 ATP 水平都可以有效地逆转葡萄糖诱导的多黏菌素耐药性。我们的工作证明了葡萄糖在 HiAlc 中诱导多黏菌素耐药的机制，从而为开发治疗由 HiAlc 引起的非酒精性脂肪性肝病的有效方法奠定了基础。HiAlc 可以利用葡萄糖产生过量的内源性酒精，促进 NAFLD 的发展。多黏菌素是最后一道抗生素防线，常用于治疗碳青霉烯类耐药肺炎克雷伯菌引起的感染。在这项研究中，我们发现葡萄糖通过增加 CPS 和维持细胞内 ATP 来增加细菌对多黏菌素的耐药性；这增加了治疗由多重耐药 HiAlc 感染引起的非酒精性脂肪性肝病失败的风险。进一步的研究揭示了葡萄糖和全局调控因子 CRP 在细菌耐药性中的重要作用，并发现抑制 CPS 形成和降低细胞内 ATP 水平可以有效地逆转葡萄糖诱导的多黏菌素耐药性。我们的工作揭示了葡萄糖和调节因子 CRP 可以影响细菌对多黏菌素的耐药性，为治疗多重耐药菌引起的感染奠定了基础。
