How “evolutionary medicine” helps create drugs that prevent antibiotic resistance

How do you stop a bug from becoming a superbug? Beat it at Darwin’s game

Maksym Kozlenko, CC BY-SA 4.0 / Wikimedia Commons

Though it sounds like a plot device from a dystopian novel, the term “superbug” describes very real disease-causing microbes that have overcome the drugs normally used against them. These bugs kill over 35,000 people every year in the US alone, and the WHO considers them one of the biggest threats to global health and security.

In the arms race against microbes, scientists have begun fighting back by targeting the bugs’ most powerful weapon: the capacity to evolve. Antibiotics jam up essential proteins in bacteria, often by binding to crucial areas called “active sites.” The lock-and-key fit of these drugs makes them work with deadly precision right up until the bacteria change their locks. The liberal use of antibiotics creates dramatic evolutionary pressure, breeding superbugs with mutations in these active sites that prevent the drugs from binding.

A paper published in eLife in July describes an effort to shut down evolutionary routes to antibiotic resistance by tailoring a drug’s chemistry to preempt mutations. The idea was that, rather than waiting for evolution to render current drugs useless and require a return to the drawing board, scientists might design them to bind to essential areas within the site that tend not to mutate, prolonging their lifespan. 

Using computational chemistry, scientists tested 1.8 million chemicals for their ability to bind to a commonly targeted bacterial protein, both with and without real-life resistance mutations. They then brought the best candidates into the lab and put them to the test, pushing bacteria to evolve in response to them. In a success, the group found that one chemical dramatically weakened and delayed the bacteria’s evolution towards resistance. While the study’s specific chemical is not quite a silver bullet, its proof of principle bodes well for the use of this “evolutionary medicine” tactic in the design of future antimicrobials as well as drugs for other diseases that acquire resistance, like cancer.