Antibiotic resistance and evasion are incompletely understood and complicated by the fact that murine interval dosing models do not fully recapitulate antibiotic pharmacokinetics in humans. To better understand how gastrointestinal bacteria respond to antibiotics, we colonized germ-free mice with a pan-susceptible genetically barcoded clinical isolate and administered the antibiotic cefepime via programmable subcutaneous pumps, allowing closer emulation of human parenteral antibiotic dynamics. was only recovered from intestinal tissue, where cefepime concentrations were still inhibitory. Strikingly, “some” isolates were not cefepime resistant but acquired mutations in genes involved in polysaccharide capsular synthesis increasing their invasion and survival within human intestinal cells. Deleting involved in capsular polysaccharide synthesis mimicked this phenotype, allowing increased invasion of colonocytes where cefepime concentrations were reduced. Additionally, “some” mutant strains exhibited a persister phenotype upon further cefepime exposure. This work uncovers a mechanism allowing “select” gastrointestinal bacteria to evade antibiotic treatment.

中文翻译：

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敏感细菌可以在哺乳动物胃肠道的抗生素治疗中存活下来，而不会产生耐药性

由于小鼠间隔给药模型不能完全重现人类中的抗生素药代动力学，抗生素耐药性和逃避性尚不完全了解且复杂化。为了更好地了解胃肠道细菌对抗生素的反应，我们用泛敏感基因条形码临床分离株定植无菌小鼠，并通过可编程皮下泵施用抗生素头孢吡肟，从而更接近地模拟人类肠外抗生素动态。仅从肠道组织中回收，其中头孢吡肟浓度仍具有抑制作用。引人注目的是，“一些”分离株并不对头孢吡肟产生耐药性，而是在参与多糖荚膜合成的基因中获得了突变，从而增加了它们在人类肠道细胞内的入侵和存活。删除参与荚膜多糖合成的行为模仿了这种表型，从而增加了结肠细胞的侵袭，其中头孢吡肟浓度降低。此外，“一些”突变菌株在进一步接触头孢吡肟后表现出持续表型。这项工作揭示了一种允许“选择”胃肠道细菌逃避抗生素治疗的机制。