Rodrigues Marinelle, Sabaeifard Parastoo, Yildiz Muhammed Sadik, Lyon Adam, Coughlin Laura, Ahmed Sara, Poulides Nicole, Toprak Ahmet C, Behrendt Cassie, Wang Xiaoyu, Monogue Marguerite, Kim Jiwoong, Gan Shuheng, Zhan Xiaowei, Filkins Laura, Williams Noelle S, Hooper Lora V, Koh Andrew Y, Toprak Erdal
Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Department of Pediatrics, Division of Hematology/Oncology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Cell Host Microbe. 2024 Mar 13;32(3):396-410.e6. doi: 10.1016/j.chom.2024.01.012. Epub 2024 Feb 14.
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 Escherichia coli clinical isolate and administered the antibiotic cefepime via programmable subcutaneous pumps, allowing closer emulation of human parenteral antibiotic dynamics. E. coli was only recovered from intestinal tissue, where cefepime concentrations were still inhibitory. Strikingly, "some" E. coli 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 wbaP 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.
抗生素耐药性和逃避机制尚未完全明了，且由于小鼠间隔给药模型不能完全重现人类体内的抗生素药代动力学，这使得情况更为复杂。为了更好地理解胃肠道细菌对抗生素的反应，我们用一种对所有抗生素敏感的、带有基因条形码的大肠杆菌临床分离株对无菌小鼠进行定殖，并通过可编程皮下泵给予抗生素头孢吡肟，从而更接近地模拟人类肠外抗生素动态。大肠杆菌仅从肠道组织中回收，而肠道组织中的头孢吡肟浓度仍具有抑制作用。引人注目的是，“一些”大肠杆菌分离株对头孢吡肟不耐药，但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侵袭和存活能力。删除参与荚膜多糖合成的wbaP基因可模拟这种表型，使头孢吡肟浓度降低的结肠细胞侵袭增加。此外，“一些”突变菌株在进一步接触头孢吡肟后表现出持留菌表型。这项研究揭示了一种机制，使“某些”胃肠道细菌能够逃避抗生素治疗。
