Penicillin attacks with a calculated strike, splitting open cell walls. Kanamycin sends a bacterium's protein assembly line into mayhem. Ciprofloxacin dices a microbe's DNA into a genetic hash. Like trained snipers, each of these common antibiotics seems to dispatch bacteria with a simple tactic: Target a high-profile molecule crucial to survival and, with a single, clean shot, defeat the whole cell.

For decades, this notion of how antibiotics kill has guided the design and deployment of drugs that have saved countless lives. Since scientists introduced penicillin in the 1940s, antibiotics have tamed some of the most deadly microbes into mild nuisances. Bacterial infections that cause tuberculosis, pneumonia and diarrhea, the three leading killers in the United States a century ago, have become curable or rare in the developed world.

But after myriad clinical victories, some scientists are questioning what we really know about the modus operandi of these bacterial assassins. In 2007, researchers proposed that, in addition to direct hits, antibiotics rev up cellular power plants and generate explosive waste. The resulting biochemical chaos might be as important to an antibiotic's deadly force as the better-studied precision tactics. The intriguing idea of antibiotics as sloppy killers created a buzz followed by a heated controversy in an otherwise sedate corner of science, says Gerry Wright, who studies antibiotic resistance at McMaster University in Hamilton, Canada.

A string of studies have come out for and against the theory, with more under way. Last year, two critical studies sparked widespread skepticism of the science behind the theory. But the clash hasn't deterred some scientists from digging further, in hopes that the fresh perspective could lead to new therapies.

Chief among them is systems biologist James Collins of Boston University, who first proposed the controversial theory. Most scientists, he says, thought that they understood how antibiotics kill. But scientists may know only a "tiny, narrow slice of what's happening," he says.

That might not be bad news: Understanding these unseen complexities of how drugs actually kill could inspire a new generation of desperately needed treatments as mounting numbers of bacteria become resistant to antibiotics.

In an evolutionary arms race with drug development, some microbes have evolved to guard or disguise prominent drug targets. Other bacteria have come up with ways of simply deporting drugs from their cellular borders. Health experts around the world have warned that modern medicine is losing a war that most thought was already won. In the United States, about 2 million people get sick with a drug-resistant bacterial infection each year and 23,000 or more die. As those numbers rise, bacteria keep developing new defenses. Some tuberculosis infections, for instance, can withstand assaults by every drug in a physician's arsenal.

In response, researchers are busily drawing up blueprints for new antibiotics and picking out new molecular targets to attack. But the efforts have been slow, scientifically challenging and expensive. Between 1998 and 2012, the U.S. Food and Drug Administration approved 14 new antibiotics. Only four had novel mechanisms.

New thinking about how old drugs actually kill could speed the development of new therapies, says Collins. If collateral damage is important in killing microbes, then figuring out ways to increase that damage could help extend the usefulness of existing drugs. Collins envisions antibiotic sidekicks that would stir up molecular trouble in the cell, creating a combination therapy that would make existing antibiotics more lethal.

The idea is to restore the effectiveness of current antibiotics as opposed to discovering a new class of antibiotics, says Jeff Wager, president of EnBiotix, a Boston company developing drugs based on Collins' work. …