Many important antibiotics are becoming less effective against bacterial infections; as bacteria continue to evolve, they gain and share resistance genes that enable them to evade the drugs. And while antibiotics are meant to kill bacteria, recent research is has suggested that antibiotics can actually trigger changes in bacterial cells that promote their survival. This work, which analyzed the interaction between Escherichia coli, a common cause of urinary tract infections (UTIs), and cirpoflaxin, an anitbiotic often used to treat UTIs. The findings have been reported in Nature Communications.
Ciproflaxin seems to promote cellular processes that encourage resistance, in part by reducing the levels of a cellular fuel called ATP. In this study, the researchers engineered two strains of E. coli: one burned ATP constantly, and another strain constantly burned the cellular fuel known as NADH. Next, these strains, as well as unmodified E. coli were exposed to ciproflaxin. Surprisingly, cellular respiration actually went up in the modified cells, and they began producing reactive oxygen species, which can damage cells and DNA.
But many of the modified bacteria actually survived. The researchers found that ten times as many cells lacking fuel ended up surviving ciproflaxin exposure compared to unmodified cells. The cells that lived, so-called persisters, can hang out in the body and cause another infection when the antibiotic is gone.
"Antibiotics can actually change bacterial metabolism...People expected a slower metabolism to cause less killing," said first study author Barry Li, a graduate and medical student at Rutgers New Jersey Medical School. "We saw the opposite. The cells ramp up metabolism to refill their energy tanks and that turns on stress responses that slow the killing."
Additional work showed that the bacteria that survived had activated the stringent response, which reprograms stressed cells. These stressed cells could then mutate faster to evolve drug resistance.
As E. coli strains were exposed to increasingly higher ciprofloxacin doses, the drug stopped working on the stressed cells four rounds prior to unmodified cells.
"The changes in metabolism are making antibiotics work less well and helping bacteria evolve resistance," said senior study author Jason Yang, an assistant professor at Rutgers.
Early experiments have suggested that other antibiotics like gentamicin and ampicillin reduce ATP as well. So this effect could be seen in many bacterial pathogens.
The researchers noted that new antibiotic candidates should be screened to see how much they reduce cellular fuel levels. Drugs that stop bacterial evolution, block stress pathways, or reduce reactive oxygen species may also be beneficial. And finally, it may not be the best approach to hit bacterial infections with high drug doses; these high doses might trigger stress that helps bacteria survive.
Sources: Rutgers University, Nature Communications