Major Advance Reported in Understanding Antibiotic Resistance

Scientists at the University of Montana (UM) and the University of Washington have discovered how pathogenic bacteria resist antibiotic treatment and recently published their findings in an article titled (“Entropically-driven aggregation of bacteria by host polymers promotes antibiotic tolerance in Pseudomonas aeruginosa”) in the Proceedings of the Natural Academy of Sciences.

“Bacteria causing chronic infections are generally observed living in cell aggregates suspended in polymer-rich host secretions, and bacterial phenotypes induced by aggregated growth may be key factors in chronic infection pathogenesis. Bacterial aggregation is commonly thought of as a consequence of biofilm formation; however, the mechanisms producing aggregation in vivo remain unclear. Here we show that polymers that are abundant at chronic infection sites cause bacteria to aggregate by the depletion aggregation mechanism, which does not require biofilm formation functions. Depletion aggregation is mediated by entropic forces between uncharged or like-charged polymers and particles (e.g., bacteria),” write the investigators.

“Our experiments also indicate that depletion aggregation of bacteria induces marked antibiotic tolerance that was dependent on the SOS response, a stress response activated by genotoxic stress. These findings raise the possibility that targeting conditions that promote depletion aggregation or mechanisms of depletion-mediated tolerance could lead to new therapeutic approaches to combat chronic bacterial infections.”

“Antibiotic resistance is a major problem,” says Patrick Secor, Ph.D., assistant professor in UM’s division of biological sciences and lead researcher on the paper. “However, it is often the case that if you take bacteria that survive antibiotic treatment from someone’s infected lungs and treats those same bacteria with antibiotics in the lab, the bacteria die. We wanted to understand why.”

We found that bacteria living in high concentrations of polymers get a little stressed out,” adds Lia Michaels, a researcher at UM and co-author of the paper. “Basically, the polymer-rich environment activates stress responses in the bacteria, causing them to tolerate higher levels of antibiotics.”

“I like to compare it to the stress our bodies undergo when we exercise,” notes Dr.  Secor. “Exercising today allows you to run a little further or lift a little more weight later on. This is analogous to the stress responses turned on in bacteria living in airway mucus—exposure to stress today allows the bacteria to survive the stress of antibiotic exposure later on.”

The researchers found that stress responses induced by mucus polymers pressing on the bacteria were a result of mild DNA damage in the bacterial cells.

“One thing that this DNA damage did was slow bacterial growth,” says Laura Jennings, Ph.D., UM research assistant professor and co-author of the paper. “Because most antibiotics work best on rapidly dividing cells, these slow-growing bacteria were more difficult to kill with antibiotics.”

The researchers speculate that the mechanisms by which polymers turn on bacterial stress responses could be targeted therapeutically to treat long-term bacterial infections.

“Our hope is that we could come up with new ways to treat bacterial infections or increase the efficacy of antibiotic treatment,” according to Dr. Secor.