Whatever Doesn’t Kill You...
How superbugs arise, and what to do about it
In the battle against infectious disease, the widespread use of antibiotics has inadvertently created superbugs that are impervious to many of medicine’s first-line defenses.
Scientists have long thought that such drug resistance arises because of an evolutionary arms race, with bacteria developing genetic immunity one-by-one to each drug that clinicians hit them with. But many researchers are starting to form a resistance movement against this traditional view.
“There’s very much a dogma of how we think resistance is engendered, but when you go to a molecular level we really don’t understand it,” says Deborah Hung, a physician-scientist at Massachusetts General Hospital in Boston. “We’re really at a point where we need a paradigm shift in how we think about antibiotics.” Two recent studies open up such a possibility.
In 2007, Boston University bioengineer James Collins and his graduate student Michael Kohanski were studying the death pathways by which a range of antibiotics go about wiping out bacteria. They realized that all the drugs that kill bacteria—but not the drugs that merely halt bacterial growth—triggered the production of the exact same, deadly free radical molecules, irrespective of the drugs’ individual modes of action. The researchers then wondered, if the free-radicals at high doses kill the bacteria, what would happen if the bacteria only formed low levels of these charged molecules?
Collins and Kohanski exposed the microbes to sublethal levels of antibiotics, and discovered that the bugs still produced the highly reactive molecules but at concentrations that were beneficial rather than fatal—the bacteria now became resistant to a whole suite of different drugs instead of dying off. That’s because the lower levels of free-radicals mutated the bacterial DNA without killing the bugs, which allowed the microbes to more rapidly acquire drug-resistant traits.
“It’s a little scary,” says Kohanski, who published the work earlier this year in the journal Molecular Cell. “It changes how you think about what’s going on when you throw an antibiotic onto a cell.” Collins’s team is now working to discover ways of inhibiting the DNA repair mechanism and controlling the levels of free radicals to prevent bacteria from adapting to our medicinal arsenal.
Troublingly, it’s not just in the laboratory where exposure to one drug is causing resistance against another. Two years ago, a Canadian team led by Michael Silverman of the Lake-ridge Health Centre in Oshawa, Ontario, reported that remote South American villagers treated with a common malaria drug carried high levels of bacteria that were resistant to the widely used antibiotic ciprofloxacin—also known as Cipro—even though the people had never taken the antibiotic. “There are multiple places where the unintended consequences of antibiotics can occur,” says Silverman. Although the Boston University researchers did not specifically test Cipro in their studies, they suspect that the observed drug resistance could have similarly arisen because of free radicals.
In a separate effort to find novel ways to prevent the evolution of antibiotic resistance, Roy Kishony, a systems biologist at Harvard Medical School in Boston, has been combining different drugs together. He has mixed and matched more than 20 antibiotics and found that some drug cocktails do not work quite as expected. In some cases, the drug combos are super-potent; in other cases, however, two drugs do not work as well in parallel. In the latter case, “it’s somewhat as if one drug is a partial anti-drug to another,” explains Kishony. “When the two drugs are put together they’re still effective, but they’re less effective than one drug is on its own.”
In the long run, that’s not necessarily such a bad thing, Kishony says. Although the drugs might not kill the microbes as fast, it’s far less likely that the bugs will develop resistance. “If one drug is an antidote to the other, then becoming resistant to one drug could have a negative impact [for the bacteria] because you lose the protective effect,” he says.
Backed by a $100,000 Gates Foundation Grand Challenges exploration grant, Kishony is now searching for agents that not only neutralize drug resistance but make it evolutionarily disadvantageous for the bacteria. Again, Collins and Kohanski think that the production of free radicals might be driving the changes in drug synergy, although this idea still needs to be tested.
Insight into the complexities of antibiotics “could have huge clinical implications,” notes Hung. For instance, it could affect dosage levels of antibiotics, what molecular pathways to pursue and how to combine assorted therapies, she says. “At the end of the day, it could greatly affect how we use antibiotics.” So, with the right strategies and a better understanding of microbial tactics, we just might win the war against resistance.
