Bacteria are fast evolving resistance to antibiotics, which is fast-tracking us to a future where our best drugs no longer work and simple infections become life-threatening once again. While new antibiotics are in the works, the bugs will eventually develop resistances to those too, so a longer term strategy might be to prevent them from evolving in the first place. A new study has found that bacteria use clever gambles to adapt – and showed how we could rig the game in our favor.

Environmental pressure underlies natural selection. As conditions get tough, many organisms die out, while the survivors may be saved thanks to random mutations in their genes that just so happen to give them an edge. These are then passed on to future generations, so that a species as a whole soon evolves to deal with the initial stressful conditions.

In the case of bacteria, those stressful conditions include antibiotics. At first these drugs may be effective against the bugs, but if any survive the onslaught, they can multiply and pass on their good genes to others. Eventually, entire populations are resistant to certain antibiotics, and we humans need to come up with new ones. It's an arms race, and one that we can't really win in the long run.

For the new study, the researchers set out to break the cycle.

"We wanted to understand the molecular mechanism underlying the evolutionary arms race that pathogenic bacteria wage against our immune systems, and against antibiotics," says Susan Rosenberg, senior author of the study. "This is motivated by the hope of being able to make or identify a fundamentally new kind of drug to slow bacterial evolution. Not an antibiotic, which kills cells or stops their proliferation, but an anti-evolvability drug, which would slow evolution, allowing our immune systems and drugs to defeat infections."

To investigate, the researchers exposed E. coli to low doses of ciprofloxacin, an antibiotic that triggers DNA breaks, and the response was fascinating. The team found that between 10 and 25 percent of the bacteria began generating high levels of toxic molecules known as reactive oxygen species (ROS).

Why would bacteria produce molecules that could kill them? It turns out, they were making the stressful environment even more stressful, effectively giving themselves an evolutionary boost. And it worked – as a stress response, this sub-population of E. coli was able to make its DNA repairs less accurate and more error-prone, increasing the chances of random mutations. That in turn raised its chances of developing a new advantage.

Perhaps the most clever thing about it is the fact that only up to 25 percent of the bacteria were experimenting with ROS molecules. Essentially, the colony was creating a subpopulation of gamblers that took risks to try to find a solution for the greater good.

"This particular mechanism is likely to be important for resistance to quinolones – very widely used antibiotics for which clinical resistance is common and occurs by new mutations in the clinic," says Rosenberg. "It is likely also to illuminate formation of resistance to other antibiotics, in which the main route to resistance is new mutations, as opposed to those antibiotics for which the main route is acquisition of resistance genes from other bacteria."

To test how one of these proposed "anti-evolvability" drugs might work, the team then combined the antibiotic with a drug called edaravone, which reduces ROS. Sure enough, that was found to prevent the gambler subpopulation from creating the stress response, and slowed down the mutations in the bacteria. Importantly, the antibiotic itself continued to work just fine.

"These data serve as a proof-of-concept for small-molecule inhibitors that could be administered with antibiotics to reduce resistance evolution by impeding differentiation of gamblers, without harming antibiotic activity," says Rosenberg. "Drugs like this could be used with standard antibiotics to slow evolution of resistance. These could potentially extend the use of current antibiotics, and possibly work as mono-therapies by tilting the evolutionary battle in favor of the immune system."

The research was published in the journal Molecular Cell.

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