What Comes After Antibiotics? 5 Alternatives to Stop Superbugs

"Superbug" bacterial infections that are resistant to common antibiotics are increasing at an alarming rate. But traditional antibiotics aren't the only way to battle dangerous germs. Biomedical scientists are investigating new additions to their arsenal.

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What Comes After Antibiotics? 5 Alternatives to Stop Superbugs
In the realm of human health, few developments are scarier than the growing uselessness of antibiotics. These miracle drugs have kept killer diseases in check for decades, saving millions of lives. Fortunately, antibiotics still work—most of the time. And though we are winning battles against germs, scientists fear that we are starting to lose the war.

According to a 2013 report from the Centers for Disease Control and Prevention, more than two million people in the United States now come down with antibiotic-resistant superbug infections every year. At least 23,000 victims die annually. And harmful bacteria and fungi are evolving resistance to deployed antibiotics at a quicker pace than we can come up with new drugs. From 1980 to 2000, the Food and Drug Administration (FDA) approved more than 50 new antibiotics. Since then, the number approved is less than 10—and, since 2010, zero.

"We have to do something, because the old antibiotic approach is failing," says Ry Young, director of the Center for Phage Technology at Texas A&M University. "The problem is becoming worse, and becoming worse faster."

In the arms race with pathogens, here are some of our most promising new weapons.
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Young and his colleagues at Texas A&M aim to unleash bacteria's age-old nemeses called bacteriophages, or phages for short. Phages are simply viruses that infect and kill bacteria. They are ubiquitous in nature and in our bodies—astonishingly, Young notes, more than 90 percent of the DNA found in us belongs to phages. All those phages are parasitizing the trillions of resident bacteria within us; those bacterial cells outnumber our "own" by about 10 to one.

Phages do not cause human illness, but for any kind of bacterium, there are often dozens of phages that harry it. Figuring out which kinds work best and could be produced economically by drug companies will take some time, but the benefits of "phage therapy" sure look enticing.

Many phages target only a few strains or even a single species of bacteria. That's a good thing: Phages are more precise than some of today's antibiotics that kill indiscriminately, causing collateral damage in our guts by wasting good-guy bacteria. "With phages, you can target your targets rather than give yourself a broad-spectrum antibiotic," Young says. As a bonus, phages that are treating an infection crank out more phages as they replicate in the stricken bacteria. "I joke that it's the only medicine that grows," he says.

The clinical use of phages started in the 1920s and '30s, meaning it actually predated the development of antibiotics. But today, just a few countries, such as Russia and Georgia, still administer the beneficial viruses to humans, through various means including oral concoctions and via injections. What happened to phage therapy? As Young explained, phages were discovered before the advent of modern biomolecular science, and the incredible success of conventional antibiotics in the 1940s relegated phage pharmaceutical investigation to the back burner. It's hard to say when we'll see phage therapy take hold in the U.S. because of intellectual-property and FDA regulatory hurdles, but Young remains hopeful.
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Although ancient civilizations, from Persia to Rome, didn't know why the treatment worked, it was known that copper and silver vessels are effective at disinfecting water and preserving food. Today we know the reason: Exposure to metals can sabotage cellular chemistry. Of course, in high enough doses metals can wreck human health, too, which is why it would be tricky to use, say, metal-based antibiotics in pill form without also poisoning a human host. Instead, metals could prove handy at slaying germs on our skin, in wounds, and on medical equipment.

Currently, some labs and pharmaceutical companies are trying to incorporate metals into bandages to prevent nasty infections at the site of a wound, which can lead to the deadly, body-wide inflammation called sepsis, a big problem around the world. "Sepsis from wounds kills more people than cancer in most countries," says Raymond Turner, a professor of biochemistry at the University of Calgary and author of a recent review on metals that serve as antibacterials. Clinical trials have also shown that using silver-oxide-coated endotracheal tubes and silver-alloy catheter tubes cuts down on infections acquired by patients in hospitals.

Other researchers are investigating metallic antibiotics with the potential to skirt the human toxicity issue and harm only bacterial cells. In that regard, a promising metal is gallium. Bacteria can uptake the metal in place of the iron they often steal from our red blood cells. Gallium, however, does not function biochemically as iron does; it cripples bacterial cellular functions. Intriguing ongoing research focuses on giving a gallium compound to cystic fibrosis sufferers as an innovative way to treat their frequent lung infections.
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Another up-and-coming way to kill bacteria is to hijack the armaments they use against each other when muscling for resources and real estate. An overlooked group of these biochemicals is known as bacteriocins. These antibacterial agents differ from the classical, natural antibiotics derived from bacteria, such as tetracycline, that are complexly structured. Bacteriocins are small proteins encoded for by single genes.

Bacteriocins possess many of the same traits that have made conventional antibiotics so successful. They can zero in on individual bacterial species, or provide broad-spectrum, carpet-bomb-style killing of many microbes. They have low toxicity in people but are very potent against bacteria, thanks to evolutionary honing.

"The logic is that bacteria occupying the same environmental niche have been competing against one another for millennia and so will have evolved highly effective antimicrobials," says Paul Cotter, a scientist at the Teagasc Food Research Centre in Cork, Ireland, who was lead author on a 2013 review study on bacteriocins. Also, as with today's antibiotics, bacteria can evolve resistance to bacteriocins. But because bacteriocins are relatively simple, they can be readily bioengineered to regain their effectiveness, Cotter says.

A twist on the bacteriocins concept: These bad-germ-killing chemicals could be produced in the body by intentionally introduced beneficial bacteria. Some of the probiotics you hear so much about these days happen to do just this.

To date, bacteriocins have found limited use in treating animals, though several human trials in the works could lead to medicines down the road.
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Persister Killers
Persister cells are a major reason why some infections can't be beat. While bacterial cells can enter an inactive state, during which time their only purpose is to survive, typical antibiotics go after cells' activities. That means that these dormant persisters are impervious to antibiotic attacks, and when these hardy cells wake back again, infections return.

A recent study has revealed a way to knock out pernicious persisters. Certain compounds can flip switches in persister cells, turning specific functions on again. A compound called ADEP4, for instance, activates an enzyme in dormant cells of one of the worst superbugs, methicillin-resistant staphylococcus aureus (MRSA). The enzyme indiscriminately chops up proteins, essentially making the cells auto-destruct.

"Instead of approaching the problem in the conventional sense of corrupting active mechanisms, you instead activate something within the cell to get it to kill itself," says Brian Conlon, a postdoctoral researcher at Northeastern University and lead author of the study.

Bacterial cells readily develop resistance to ADEP4. But in the process, they become far more vulnerable to conventional antibiotics, because taking the ADEP4-targeted enzyme offline weakens the cell in various ways. Therefore, a one-two punch of ADEP4 and routine antibiotics successfully cleared infections in the study. The hope is that similar such combos will clean the clocks of other bacteria in the future.
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Courtesy of J.Carr/CDC; T.Gianoulis and D.Massa/Yale
One more auspicious antibiotic alternative is PPMO, or peptide-conjugated phosphorodiamidate morpholino oligomer. PPMOs bind to and "silence" microbial genes in either RNA or DNA. In that way, these biochemicals can shut down germs by blocking either essential survival genes or the genes that confer antibiotic resistance, thus serving up bacteria to be slaughtered by standard meds.

PPMOs are lab-made and synthetic. Accordingly, they can be quickly and easily tailored to target specific genes in the offending bug of interest. "That's the beauty of it—you can turn around in a week and create a new drug," says Bruce Geller, a professor of microbiology at Oregon State University. Geller was lead author of a recent study that revealed a PPMO's success in cell cultures and mice against Acinetobacter, a source of respiratory and wound infections, some of which are antibiotic-resistant.

Before coming to a pharmacy near you, PPMOs will have to undergo much more development and then testing in humans. Geller, along with other researchers, is optimistic about our future prospects against the bacteria that have begun evolutionarily outwitting us.

"Of all the standard antibiotics made over the last 60 years, all of them target only about five components of bacteria," Geller says. But with PPMOs and the rest of the new alt-antibiotic wave, "hundreds, thousands of components might be targeted" in bacteria, and will become vulnerable to our counterattacks.
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