A newly discovered mechanism of antibiotic resistance helps explain how bacteria have so quickly undermined medicine's front-line defenses, turning miracle drugs into duds in just a few decades.

Scientists have long known that exposing bacteria to the right antibiotics will kill most of them, but leave a few mutants that happen to resist the drug better than the rest. These mutants go on to multiply, and eventually the whole strain evolves resistance.

Now a new study paints a more complicated picture of antibiotic resistance. Bacteria don't just develop resistance to one drug at a time, but to many – and at accelerated rates. That's because antibiotics boost bacterial production of free-radical oxygen molecules that damage bacterial DNA. Repairs to the DNA cause widespread mutations, giving bacteria more chances to randomly acquire drug-resistant traits.

"You have a wide range of mutations being introduced across the genome. Some afford resistance to that antibiotic. Some afford resistance to other antibiotics," said James Collins, a Boston University biomedical engineer who described the mechanism in a paper published Feb. 11 in Molecular Cell. "It would happen anyways, but this process is accelerating it."

Drug resistance is a serious public health concern. According to the federal Centers for Disease Control and Prevention, 70 percent of 1.7 million infections acquired in hospitals every year are resistant to at least one drug. Those infections annually kill 99,000 Americans – more than double the number that die in car crashes.

Drugs that once destroyed almost any bacteria now kill only a few, or don't work at all. In the case of some drugs, like Cipro, the decline is dramatic: Where in 1999 it worked against 95 percent of E. coli, it treated only 60 percent by 2006. Against lung infection-causing Acinobacter, its effectiveness fell by 70 percent in just four years.

Though drug resistance is ultimately inevitable, conventional wisdom holds that antibiotics consumed at suboptimum doses hasten the process. Bugs that would have succumbed to a larger dose live to multiply, pushing the strain as a whole closer to resistance. That happens when a prescription goes unfinished, or when antibiotics used on farms enter food and water at low levels.

The conventional wisdom isn’t wrong, but the new findings suggest that drugs push bacteria towards resistance even more rapidly, and in more ways, than was thought.

"It's a really important paper. It underscores that we don't fully know how antibiotic resistance is engendered," said Harvard University molecular biologist Deborah Hung. "If you treat with low concentrations of antibiotic, the bugs respond by increasing their mutation rates."

In earlier research, Collins' team showed that antibiotics don't only kill bacteria as expected – by corroding cell walls, messing with DNA and blocking proteins – but by triggering the release of free-radical oxygen molecules. Thanks to an extra electron, the free radicals bind easily and corrosively with other molecules, and prove as lethal as the drugs themselves.

For the latest study, the researchers tested whether free radicals might also affect drug resistance by using sublethal doses of five common antibiotics on Staphylococcus aureus, the annual cause of 500,000 infections in the United States, and two strains of E. coli, including one taken from a patient.

The free radicals caused DNA damage that didn't kill all the bacteria. The bacteria's self-repair processes then introduced mutations to genes that provided resistance to many drugs, not just those being administered.

Drugs might be found that could alter bacterial DNA repair systems, but that prospect is extremely speculative, said Collins.

Hung said more research is needed to show how different bacteria respond. Mutation rates might vary between strains. It's also possible that free-radical damage also accelerates horizontal gene transfer, in which bacteria swap genes without reproducing. If so, resistance could develop faster and spread more rapidly.

"The clinical significance is not clear yet, but it certainly should make us pause and think about the way we use antibiotics," said Hung.

In recent years, public health experts have recommended that doctors use antibiotics only when necessary, and that patients complete every prescription. They've also called for dramatic cuts in the agricultural use of antibiotics.

Of the 35 million pounds of antibiotics consumed annually in the United States, 80 percent goes to farm animals. Much of it is used to treat diseases spread by industrial husbandry practices, or simply to accelerate growth. As a result, farms have become giant petri dishes for superbugs, especially multidrug-resistant Staphylococcus aureus, or MRSA, which kills 20,000 Americans every year – more than AIDS.

Alarming cases of farm-based MRSA and other diseases led to a proposed Congressional law restricting the use of agricultural antibiotics. That bill, supported by the American Medical Association and American Public Health Association, is opposed by farm lobbyists and remains stuck in committee.

"We need to look carefully at situations where antibiotics are used in agriculture and water supplies," said Collins. "The benefits may not outweigh the potential harm we're doing by creating stronger, more problematic microbes."

Image: Samantha Celera/Flickr

See Also:

Citation: "Sublethal Antibiotic Treatment Leads to Multidrug Resistance via Radical-Induced Mutagenesis." By Michael A. Kohanski, Mark A. DePristo, and James J. Collins. Molecular Cell, Vol. 37 No. 3, February 11, 2009.

"The Fast Track to Multidrug Resistance." By Benjamin B. Kaufmann and Deborah T. Hung. Molecular Cell, Vol. 37 No. 3, February 11, 2009.

Brandon Keim's Twitter stream and reportorial outtakes; Wired Science on Twitter. Brandon is currently working on a book about ecological tipping points.