A new strategy to combat antibiotic resistance has emerged from a study led by researchers at Baylor College of Medicine. Published in the journal Molecular Cell, the report reveals for the first time how bacteria evolve mutations that confer antibiotic resistance and that this process can inhibited with FDA-approved drug edaravone. “Antibiotic resistance is one of the most urgent threats to public health. Bacteria develop resistance thanks to the appearance of new mutations in their DNA that allow bacteria to overcome the deadly effects of the antibiotic.
Mutations conferring antibiotic resistance
Traditionally, antibiotic resistance has countered with new antibiotics. In this study, however, the researchers looked to discover and then inhibit the molecular mechanisms that induce mutations conferring antibiotic resistance. They treated laboratory cultures of the bacterium Escherichia coli with low doses of the antibiotic ciprofloxacin; which are to induce new mutations that confer antibiotic resistance.”In this system, they investigated in great detail the molecular pathways that were activated as the bacteria evolved antibiotic resistance.”
Pribis, Rosenberg and their colleagues discovered that ciprofloxacin-induced DNA breaks; which followed by bacteria releasing a burst of toxic compounds called reactive oxygen species. These compounds activated a general stress response that triggered error-prone DNA-repair; which resulted in mutations.
“The researcher prised to find that the burst of reactive oxygen occurs only in 10 to 25 % of the bacterial population; that only these cells follow the next molecular steps that conclude in gene mutations. “Some of these mutations may confer antibiotic resistance, but others will not and may lethal for the bacteria. While these mutating ‘gambler’ cells sort of roll the dice on their genome generating mutations; the remaining bacteria do not mutate.”
The Low doses of antibiotic
Therefore these findings suggest that bacteria that are exposing to low doses of antibiotic set in play a molecular strategy; that confers a survival advantage to the bacterial population as a whole and is likely disadvantageous for some of the bacteria in an infection, said Rosenberg. While a small segment of the population, the gamblers, takes the risk of generating mutations; the rest of the bacteria stay stable and do not follow that path. As a result, if those that mutated do not survive; there still is a portion of the original population that will.”
“They realize that there are FDA-approved drugs that reduce the production of reactive oxygen species, one of the crucial steps leading to mutations,” Pribis said. “They found that the drug edaravone, which is used for treating amyotrophic lateral sclerosis and stroke; would fit in the molecular mechanisms we had described inhibiting the production of reactive oxygen species.”
“Indeed, when they tried it, it slowed down the development of mutations in bacterial cultures without losing its ability to kill bacteria. In conclusion, the drug prevented the rapidly evolving ‘gambler’ cell subpopulation from forming,” Rosenberg said. The researchers plan to investigate next whether this drug is able to slow the course of an infection, with or without antibiotic treatment, in models of infections.