Bacterial Mutants Take One for the Team

It’s been a perpetual arms race between bacteria and doctors since synthetic antibiotics were first introduced in the early 20^th Century. Now, research has uncovered a surprising strategy bacteria use to outpace those drugs: charitable mutants. Instead of resistance residing in every individual bacterium, the power to fend off drugs is held by a select few. At the cost of their own fitness, these mutants produce a chemical that shields the entire community from antibiotic danger — a newly discovered tactic in the battle of mutants versus humans.

These novel findings help explain how bacteria develop resistance and could eventually change the ways that doctors prescribe antibiotics to fight infections, some experts suggest.

Lead author Henry H. Lee, a biomedical engineering Ph.D. candidate at Boston University, published the research in the September 2 issue of Nature. Lee administered increasing concentrations of antibiotics to a population of common intestinal bacteria known as E. coli, monitoring its response daily. Rather than assess the entire colony at the final stage of infection, Lee examined individual bacteria to examine how resistance emerges. He found that two general sects appeared in the community: highly resistant mutant bacteria and their weaker neighbors.

After ten days of barraging the bacteria with more and more antibiotics, Lee discovered that the colony could withstand nearly five times the initial amount of drugs, originally dosed to kill no more than 60% of the bacterial population. Its surprising survival was due to a few resistant mutants releasing high levels of indole, a defensive molecule that effectively shielded their neighbors from attack. The mutants’ counterstrike strategy taxed their own energy stores for the good of the community.

Such altruistic behavior—an unselfish act benefiting others—challenges the “every bacteria for themselves” thinking that characterized past studies, Lee said. “The population seems to have a collective behavior, although why they’re doing it is more of an interesting philosophical question.”

Biophysicist Hyun Youk of the Massachusetts Institute of Technology agreed that the “why” behind the mutants’ self-sacrificing behavior is not easily answered. “We don’t really know why we see altruism in bacteria,” said Youk, who was not involved in the research. He speculated that the mutant bacteria’s altruistic behavior might aid in the survival of the species as a whole, thus indirectly benefiting the altruists and maintaining the mutation in the population.

Regardless of why the mutants take this defensive strategy, the study’s “groundbreaking evidence of resistant bacteria lending a hand to their non-resistant cousins goes beyond the classical picture of ‘survival of the fittest’ model of thinking,” according to Roy Kishony, a systems biologist at Harvard Medical School not involved in the research. Understanding and finding ways to prevent this strategy could help scientists develop new methods for combating bacterial infections, Kishony said.

Youk explained: “When you go to see a doctor, the doctor prescribes something like ‘Take three pills for a week.’ ” However, with the bacteria’s “cunning strategy” of resistance revealed, researchers might find that a tailored prescription—for example, changing the number of pills, or how often pills are taken—could be the best path to defeating an infection, said Youk. “If we change our strategies, then bacteria might have a harder time developing resistance strategies,” said Youk. Lee’s findings “certainly will change the way biologists study antibiotic resistance in the laboratory,” Youk added.

Lee said his research constitutes only the beginning for investigating the many “tricks up their sleeves” that bacteria possess. He added that medical counterattacks to our bacterial opponents are anything but straightforward. As Lee explained, if the weapon of resistance—indole—is blocked, bacterial mutants benefit because the metabolic cost of producing the chemical no longer taxes their ability to thrive. However, allowing indole production to continue means that weaker bacteria will continue to prosper by way of their altruistic neighbors and possibly acquire resistance strategies of their own. This complexity means that potential changes in drug therapies will have to be carefully weighed before appearing on the doctor’s prescription pad.

The double-edged resistance sword demonstrates the need to be more careful with antibiotics, Lee said. Specifically, both patients and physicians must be more diligent than ever in adhering to antibiotic guidelines. Whether manifesting as overuse or underuse, such misuse of antibiotics “is sabotaging the future of our public health,” Lee said. Both sides of the coin cause problems: physicians can fall victim to over-prescribing drugs through a “just in case” mentality, Lee explained, while patients who don’t complete their entire dosing regime of antibiotics are equally guilty of irresponsibility in underusing them. Both forms of misuse can allow bacteria to acquire stronger and more complex resistance strategies.

Bacterial resistance seems to be on the rise while the number of new antibiotics in the clinical pipeline is declining, Lee said, but he hopes that improving public awareness of more effective antibiotic use may allow time to explore new treatment strategies.

“It’s an ongoing battle,” Lee said. “We discover a new drug; [bacteria] develop a mechanism to fight it.”