A magazine for friends of the Warren Alpert Medical School of Brown University.

Stress Kills


Even some bacteria are susceptible—due to certain antibiotics.

Just as mounting stress can sicken and kill a human, it appears that the bacterium Escherichia coli can be similarly vulnerable under antibiotic treatment.

A study by Peter Belenky, PhD, assistant professor of molecular microbiology and immunology, tested three antibiotics—ampicillin, kanamycin, and norfloxacin—and found that rather than kill outright, they upset E. coli’s metabolism, creating a state of oxidative stress that ultimately breaks down the bacterium’s DNA and other key molecules. The findings, published in Cell Reports in November, have specific implications for how antibiotics can be used and improved, Belenky says. “Understanding how antibiotics kill bacteria—the very specific pathways—becomes very important for figuring out ways we can potentiate antibiotic activity with current antibiotics.”

In recent years many scientists have suggested that bacterial death stems from major metabolic disruptions. Belenky’s study, as well as a paper he co-authored earlier this year in the Proceedings of the National Academy of Sciences, were the first to test these hypotheses by making direct measurements of the metabolic products of E. coli as it suffered antibiotic attack.

In all, Belenky and his co-authors, including research assistant Benjamin Korry, tracked levels of nearly 200 metabolites in the cell. Direct chemical evidence showed that the bacteria ramped up a key energy-generating process called the TCA cycle, which in overdrive produces oxidative stress, but were eventually overwhelmed.

They also directly observed the telltale damage of oxidative stress on proteins, lipids, DNA, and RNA. By sending in glowing proteins that attach to fractured DNA, for example, the team found fatal double-strand breaks in the DNA of E. coli subjected to antibiotics—breaks that occurred much less frequently in E. coli left unhindered by the drugs.

The findings suggest several pathways to more effective treatments, Belenky says. For example, the fact that antibiotics damage DNA indicates that sublethal doses may cause genetic mutations that may promote antibiotic resistance. Scientists could learn the efficacy of an antibiotic in minutes, rather than hours, if they can look for metabolic changes. They may also be able to find ways to boost the TCA cycle into overdrive to accelerate bacterial death. Finally, because antibiotics are often given in combination, understanding which ones tamp down TCA and which accelerate it could prevent doctors from inadvertently undermining treatment regimens. Belenky says he hopes the findings can lead to more effective treatments for patients fighting infections.


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