摘要

抗生素抗性革兰氏阴性细菌需要新的抗生素。改变用途的抗真菌药物ciclopirox同样可以阻断抗生素敏感或耐多药的鲍曼不动杆菌，大肠埃希菌和肺炎克雷伯菌临床分离株，表明它不受现有抗性机制的影响。为了解ciclopirox如何阻止生长，我们筛选了大肠杆菌突变菌株，发现编码参与半乳糖补救，肠杆菌共同抗原合成和铁结合铁载体肠球蛋白运输的基因的破坏降低了所需的环吡酮的最低抑菌浓度与同基因亲本菌株相比，阻断突变体的生长。我们发现ciclopirox诱导了肠杆菌素的产生，并且这种效应受到编码UDP-半乳糖4-差向异构酶，galE或半乳糖-1-磷酸尿苷酰转移酶galT的半乳糖补救基因的缺失的强烈影响。由于ECA合成的破坏激活了荚膜合成（Rcs）磷酸化的调节，其抑制细菌聚集并促进生物膜发育，我们测试环吡酮是否阻止Rcs途径的活化。次级抑制浓度的环吡酮增加了大肠杆菌实验室K12菌株BW25113的蜂群，但对临床分离的大肠杆菌，鲍氏不动杆菌和肺炎克雷伯菌的蜂群或表面运动具有广泛不同的影响。 ciclopirox对生物膜产生没有影响，表明它不针对Rcs。总而言之，我们的数据表明，环吡酮介导的脂多糖改变可刺激肠杆菌素的产生并影响细菌的聚集。

New antibiotics are needed against antibiotic-resistant gram-negative bacteria. The repurposed antifungal drug, ciclopirox, equally blocks antibiotic-susceptible or multidrug-resistant Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae clinical isolates, indicating that it is not affected by existing resistance mechanisms. Toward understanding how ciclopirox blocks growth, we screened E. coli mutant strains and found that disruption of genes encoding products involved in galactose salvage, enterobacterial common antigen synthesis, and transport of the iron binding siderophore, enterobactin, lowered the minimum inhibitory concentration of ciclopirox needed to block growth of the mutant compared to the isogenic parent strain. We found that ciclopirox induced enterobactin production and that this effect is strongly affected by the deletion of the galactose salvage genes encoding UDP-galactose 4-epimerase, galE, or galactose-1-phosphate uridylyltransferase, galT. As disruption of ECA synthesis activates the regulation of capsular synthesis (Rcs) phosphorelay, which inhibits bacterial swarming and promotes biofilm development, we test whether ciclopirox prevents activation of the Rcs pathway. Sub-inhibitory concentrations of ciclopirox increased swarming of the E. coli laboratory K12 strain BW25113 but had widely varying effects on swarming or surface motility of clinical isolate E. coli, A. baumannii, and K. pneumoniae. There was no effect of ciclopirox on biofilm production, suggesting it does not target Rcs. Altogether, our data suggest ciclopirox-mediated alteration of lipopolysaccharides stimulates enterobactin production and affects bacterial swarming.

https://www.ncbi.nlm.nih.gov/pubmed/30633761