Though it was known in the nineteenth century that bacteria are the cause of many diseases, no effective antibacterial treatments were available back then. In 1910, Paul Ehrlich developed the first antibiotic. Bacteria are also notorious for existing antibiotic treatments. A new study is showing that bacteria that are starving tend to resist antibiotics better. During an infection there is a tendency to starve bacteria under certain conditions. How can this be reversed? "Bacteria become starved when they exhaust nutrient supplies in the body, or if they live clustered together in groups know as biofilms," said the lead author of the paper, Dr. Dao Nguyen, an assistant professor of medicine at McGill University.
A biofilm is an aggregate of microorganisms in which cells adhere to each other on a surface. Biofilm, which is also referred to as slime (although not everything described as slime is a biofilm), is a polymeric conglomeration generally composed of DNA, proteins, and polysaccharides. Biofilms may form on living or non-living surfaces and can be prevalent in natural, industrial and hospital settings.
"A chief cause of the resistance of biofilms is that bacteria on the outside of the clusters have the first shot at the nutrients that diffuse in," said Dr. Pradeep Singh, associate professor of medicine and microbiology at the University of Washington in Seattle, the senior author of the study. "This produces starvation of the bacteria inside clusters, and severe resistance to killing."
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.
Bacteria become highly tolerant to antibiotics when nutrients are limited. The inactivity of antibiotic targets caused by starvation-induced growth arrest is thought to be a key mechanism producing tolerance. The protective mechanism is controlled by the starvation-signaling stringent response (SR), and our experiments link SR-mediated tolerance to reduced levels of oxidant stress in bacterial cells. Furthermore, inactivating this protective mechanism sensitized biofilms by several orders of magnitude to four different classes of antibiotics and markedly enhanced the efficacy of antibiotic treatment in experimental infections.