Researchers studying antimicrobial resistant E. coli – the leading cause of death in humans worldwide due to antimicrobial resistance – have identified a mechanism in dogs that can render multiple classes of antibiotics ineffective.
The article, which will be published in the magazine on July 16 Applied and environmental microbiologyopens new possibilities for therapies to treat both animals and humans – and establishes clinical infections in dogs as a public health surveillance approach.
The research team analyzed more than 1,000 genomes of the drug-resistant E. coli pathogen isolated from sick dogs and identified a set of genes that evolutionary selection tests showed had become obsolete in the genome and lost their function. But in an unusual twist, the loss of function may have repurposed this set of genes to create conditions that trap antibiotics in the cell membrane of E. coli, preventing them from entering the bacteria.
“I like to think of it as a serendipitous evolutionary event, because it appears that these capsule proteins have been repurposed to capture antibiotics,” said Laura Goodman, an assistant professor at Cornell University and senior author of the paper.
“What seems to be happening is that we’re looking at a loss-of-function mutation that may produce a new phenotype that is unrelated to its original purpose,” she said.
This study can not only help improve the health of dogs, but is also an example of how dogs serve as an important model for human health.
Dogs tend to share similar E. coli strains as their owners and are treated with similar antibiotics. Two specific classes of antibiotics – cephalosporins and third-generation quinolones – are considered critical by the World Health Organization. Doctors and public health experts are particularly concerned about the overuse of these drugs in veterinary medicine; Although there are no legal restrictions on the use of these medications in dogs, great efforts have been made to promote proper management of these treatments.
The researchers hypothesized that mechanisms affecting the drug classes identified in dogs would also be important in humans, Goodman said. “When we looked for this genetic variant in human infections, we found a lot of it in hospital and public surveillance data of E. coli and Klebsiella infections in humans,” she said.
Researchers can now investigate potential new drug targets that prevent the pore in the E. coli membrane channel from closing, allowing antibiotics to move freely within the cell.
The study is unique because it provides a mechanistic insight into antibiotic resistance and fills important gaps in the surveillance of human E. coli infections using residual clinical samples from dogs collected as part of routine care, Goodman said.
The research was supported and conducted in collaboration with the U.S. Food and Drug Administration’s Veterinary Laboratory and Response Network.
