Nguyen and Singh explored an alternative mechanism.
Microbiologists have long known that when bacteria sense that their nutrient supply is running low, they issue a chemical alarm signal. The alarm tells the bacteria to adjust their metabolism to prepare for starvation. Could this alarm also turn on functions that produce antibiotic resistance?
To test this idea, the team engineered bacteria in which the starvation alarm was inactivated, and then measured antibiotic resistance in experimental conditions in which bacteria were starved. To their amazement, bacteria unable to sense starvation were thousands of times more sensitive to killing than those that could, even though starvation arrested growth and the activity of antibiotic targets.
"That experiment was a turning point," Singh said. "It told us that the resistance of starved bacteria was an active response that could be blocked. It also indicated that starvation-induced protection only occurred if bacteria were aware that nutrients were running low."
With the exciting result in hand, the researchers turned to two key questions. First does the starvation alarm produce resistance during actual infections? To test this the team examined naturally starved bacteria, biofilms, isolates taken from patients, and bacterial infections in mice. Sure enough, in all cases the bacteria unable to sense starvation were far easier to kill.
The second question was about the mechanism of the effect. How does starvation sensing produce such profound antibiotic resistance?
Again, the results were surprising.
Instead of well-described resistance mechanisms, like pumps that expel antibiotics from bacterial cells, the researchers found that the bacteria's protective mechanism defended them against toxic forms of oxyge
|Contact: Leila Gray |
University of Washington