Susceptible bacteria can survive antibiotic treatment in the mammalian gastrointestinal tract without evolving resistance.

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. [Display omitted] • A murine model that allows for closer emulation of antibiotic pharmacokinetics in humans • E. coli isolates are only recovered from intestinal tissue of mice treated with cefepime • Some E. coli acquire mutations increasing invasion and survival within intestinal cells • Select E. coli mutants exhibit a persister phenotype when further exposed to cefepime Rodrigues et al. demonstrate that Escherichia coli colonizing the murine gastrointestinal tract can evade antibiotic treatment by acquiring mutations increasing their ability to invade and survive within intestinal cells, where antibiotic concentrations are lower but inhibitory. Some mutant strains exhibit a persister phenotype enabling them to survive antibiotic exposure. [ABSTRACT FROM AUTHOR]