Humans and bacteria have been clashing for as long as both have inhabited the Earth, and for decades now, humans have had the upper hand. Starting with penicillin in 1942, antibiotics have brought previously untreatable maladies like tuberculosis under control and made surgery far safer.

But bacteria didn’t stop evolving, and infectious agents have been mutating at a rate that has begun to threaten that victory. In the United States, more than a dozen types of infections from bacteria are now resistant to all or nearly all known drugs, including clostridium difficile, which causes severe diarrhea; methicillin-resistant Staphylococcus aureus, also known as MRSA, and even a strain of the sexually transmitted disease gonorrhea. Public health experts warn that left unchecked, antibiotic-resistant infections will surpass cancer as one of the world’s biggest killers, claiming 10 million deaths annually by 2050.

Health leaders have been sounding the alarm that infectious disease could become the first big medical gain that humans eventually surrender. “This may even bring the end of modern medicine as we know it,” Margaret Chan, former director-general of the World Health Organization, warned last year.

Part of the problem is that this is one medical calamity the private sector isn’t well-suited to fix. Antibiotics are hard for drugmakers to develop, and as short-term treatments they don’t provide the same payback as pills that patients take for years. So Washington has stepped into the gap. In 2008, the National Institutes of Health warned about the rising threat of antibiotic resistance in a published report. In 2015, the Obama administration laid out a national action plan to combat antibiotic resistance.

Some of the plan was to improve policy and medical practice: developing better medical testing and surveillance, for example, and figuring out how to better use the existing antibiotics. But some of it was a radical investment in the future. To plant the seeds of new treatments, the agency encouraged medical researchers to think outside the box. What if bacteria can be defeated without using antibiotics? As part of the Obama administration’s National Action Plan for Combating Antibiotic Resistant Bacteria, NIH distributed $5 million to 24 research projects that are using unconventional, sometimes controversial therapies to try to beat bacteria.

The money, most of which went to American academic institutions and some of which went to private companies and international researchers, represents a small slice of the funding NIH spends annually on combating antibiotic resistance—about $473 million in the most recent fiscal year. It’s more a scientific way to throw spaghetti at the wall to see what sticks. Dr. Dennis Dixon, chief of the Bacteriology and Mycology Branch at the National Institute of Allergy and Infectious Diseases at the NIH, calls it a “high risk, high reward” investment—the kind of thing needed when conventional methods stop working. By spreading it around to interesting strands of research, the government hopes it can plant the seeds of new ideas.

Humans are beginning to lose the battle against dangerous bacteria like clostridium difficile, at left, and MRSA, at right, because the bacteria are mutating faster than we're developing antibiotics to treat them. Worried about the future of such "superbugs," the National Institutes of Health are funding two dozen studies around the country that are looking for "outside the box" ideas for how to win the battle against the microbes. | Getty

What do the ideas look like? Several of the projects are testing theories of how to undercut the bacteria themselves, sapping their power to infect a human body. Others use the good bacteria found in humans to go after the harmful bacteria. And others are trying to harness new technology, such as light therapy.

About one-third of the funded projects focus on the controversial but promising idea of bacteriophage therapy. Also called phage therapy, it was developed in Eastern Europe in the early 20th century but largely dropped out of sight after antibiotics came on the market. Now, U.S. scientists are taking a second look.

Bacteriophages (which in Greek means “bacteria eater”) are tiny viruses that live in toxic environments like dirty water and sewage; they can kill specific bacteria with the help of enzymes called lysins to destroy the bacteria’s cells. In bacteriophage therapy, scientists match the right bacteriophage with the kind of bacteria it can kill; if it works, the phages kill the bad bacteria but keep the body’s good bacteria intact. (That’s an important difference from antibiotics, which cause problems of their own by killing beneficial microbes.) The University of California at San Diego said in April that it successfully treated the first American patient with phage therapy, a 69-year-old man who had developed a multidrug-resistant strain of Acinetobacter baumannii during a trip to Egypt.

But there are many skeptics of phage therapy, particularly in Western countries. A chief concern is that, unlike chemical medications perfectly composed in a lab, phages are live agents that can have unpredictable reactions in the body. So far, it is also hard to match the right phages to the right bacteria, and there is a constant threat that the bacteria will learn how to resist the phages, too.

Another strategy would essentially alter bacteria to make them harmless—neutering bad microbes so they no longer pose a threat. The idea behind these so-called anti-virulence therapies is to develop a drug that would change the structure of the bacteria, for instance by disrupting their ability to attach to the body. “The bad bacteria lives, but it can’t harm,” said David G. Thanassi, a professor and researcher at Stony Brook University in New York who received federal funding to research how to prevent bacteria from sticking to the urinary tract. “The idea of how to disarm the bacteria—there has yet to be an approach that has come to market, but there is a lot of promise in this.”

One of the potential antibiotic treatments researchers are pursuing is using "bacteriophages" — tiny viruses, like the one depicted above, that kill bacteria. When the process works, the phages kill the target bacteria without damaging so-called good bacteria. However, skeptics express concern that unlike regular antibiotics, phages are live agents that can have unpredictable reactions in the body. | Getty

Another approach, being tested by Harvard Medical School professor Michael Hamblin, is to use light and dyes to kill bacterial infections on the skin. Hamblin is studying whether photodynamic therapy can kill localized infections. Patients would be injected with a nontoxic dye that attaches to the bacteria; doctors then shine a red, blue or green fiber-optic light exactly on the dyed bacteria. The combination of dye, light and oxygen kills the bacteria. “When you put them together, it is highly reactive—it can virtually kill anything dead,” Hamblin said.

The method is already used today to combat bacteria that sit on the skin, such as those that cause severe acne and gum disease. Hamblin is trying to figure out how to use it to combat infections under the skin, such as bladder infections or those on orthopedic implants or wounds.

In an interview, Dixon declined to pick a favorite among the strategies and suggests that medicine’s response to antibiotic resistance will always require a combination of new drugs, as well as better stewardship of the existing ones and some unconventional thinking. “The approach that works will be the favorite,” he said. “We don’t know which one that is right now.”

Unlike cancer or polio, he stressed, there is never going to be a cure for bacterial infections. “These are always going to be around us; they’re always going to be a problem. That’s why we want to have a multipronged approach to dealing with them when we need to,” Dixon said. Humans and bacteria can both evolve—bacteria much more quickly—so we’ll be in some kind of Darwinian warfare for as long as we’re both on the planet.

Jennifer Haberkorn is a senior health care reporter for POLITICO Pro.

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