Science
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Defeating the superbugs: New inventions to kill drug-resistant disease

The ominous decline of traditional antibiotics has inspired new research into ways to kill bad bacteria

In the battle against disease-causing microbes, the bugs now seem to be winning. Antibiotic drugs, which were once so good at eliminating bacterial infections of all kinds, are rapidly losing the ability to control disease, a problem that gets worse every year. Last month, the World Health Organization reported that across the planet, bacteria that resist standard antibiotics are now common in urinary tract infections, pneumonia and bloodstream infections. The Centers for Disease Control and Prevention calculates that every year in the U.S., antibiotic-resistant bacteria sicken 2 million people and kill 23,000. Gonorrhea was once a snap to cure, but some cases of this sexually transmitted infection are now caused by superbugs that defy every antibiotic we have. The advance of antibiotic resistance means that routine procedures like heart surgery or joint replacements could soon become dangerous, without reliable ways to prevent infection.

At the same time, there’s a dawning realization that broad-spectrum antibiotics can also make people sick, because these powerful drugs kill beneficial bacteria that maintain health and keep disease-causing bugs in check. Only recently have researchers begun to appreciate the dangers of disrupting the healthy microbiome — the microorganisms that live on and in our bodies. It leaves us vulnerable to nasty bacteria like Clostridium difficile, which often proliferates in the digestive tract after a person takes antibiotics for an infection. Each year, almost 250,000 Americans are hospitalized because of C. difficile, and roughly 14,000 die.

The ominous decline of traditional antibiotics, together with the growing knowledge of good bacteria, has inspired a new wave of research into therapies that target and kill only disease-causing bugs. “It’s a sniper rather than a shotgun,” said David W. Martin, president of the California-based biotech company AvidBiotics. “There are two things to gain from precision drugs for bad bugs: You don’t cause the spread of resistance, and you don’t cause damage to the bugs that you need for good health.”

Precision weapons

These precision weapons take several forms. AvidBiotics is developing new, targeted compounds that use bacterial biology to zero in on disease-causing infections. The bacterium Pseudomonas aeruginosa naturally produces proteins that drill holes in other bacteria, disabling or killing them. AvidBiotics uses genetic engineering techniques to tweak these toxic compounds so that they specifically target one dangerous pathogen, like C. difficile or the Escherichia coli O157:H7 strain that causes bloody diarrhea and, sometimes, fatal kidney failure. When tested in mice, the C. difficile–fighting compound protects against infection without killing normal gut bacteria. It could be given as a preventive to certain patients before they are treated with antibiotics, or to prevent relapses, suggests Martin. The company plans to apply for regulatory permission to begin tests in humans next year.

Biomedical engineer James J. Collins of Boston University also tinkers with natural bug-fighting compounds, using the tools of synthetic biology to craft new biological weapons. His group is designing a probiotic that can detect and attack infectious bacteria. The group is engineering a biological circuit into lactobacillus — the same genus of bacteria found in yogurt and kimchi — so that it will respond to signaling molecules produced by the cholera bug with a toxin that targets and kills the microbe.

In general, treating people with broad-spectrum antibiotics to prevent infections is bad practice, because it encourages antibiotic strains to grow. Collins’ invention gets around this problem. Because the probiotic generates its toxic payload only if it senses a specific invader, Collins suggests it could be deployed as a preventive medicine during outbreaks. “You could use it as a pre-emptive, without having a person take an antibiotic, which could be expensive and toxic,” said Collins, who is director of the Center of Synthetic Biology at BU. “You can attack the infection when it’s still at a very low level, and keep the infection at bay.”

Predatory viruses

Collins and others are also experimenting with phages, predatory viruses that infect and kill bacteria. Phages were used to treat bacterial infections in the early 20th century, before antibiotics were invented. But at that time there was no good way to identify which bacteria were causing an infection, and phages are highly selective, tuned to infect one specific type of bacterium. Because doctors could only guess which phage to use, treatments weren’t very effective. Phages were abandoned in the West but remain popular in Eastern Europe, where cocktails of different phage species can still be bought over the counter.

Today, gene sequencing can quickly identify which bacterium is causing an infection, opening up new possibilities for phage therapy. But tests of phages in human patients have been slow in coming. One small study in the United Kingdom five years ago hinted that phages might control chronic ear infections without side effects, but it was never followed up with larger trials. Nestlé Research Center conducted a study of phage therapy to treat diarrhea caused by E. coli in children, but the study was terminated last fall after a preliminary analysis of 120 patients revealed no benefit for the treatment.

Natural phages have some limitations: If injected directly into a person’s bloodstream, they tend to get sopped up by the liver and spleen before they can do their job. Because bacteria can quickly develop resistance to just one phage, the viruses should ideally be given in mixtures, which can be a challenge for industrial-scale production. The company AmpliPhi Biosciences has spent years figuring out how to produce large amounts of the right mixture of phages under high quality-control standards. “We’ve figured out optimum time conditions and conditions for growing the phage,” said CEO Phil Young.

The company has developed an inhaled phage cocktail for drug-resistant P. aeruginosa, a stubborn bacteria that infects the lungs of people with cystic fibrosis. The mix was successful in mice, and the company plans to launch a trial in humans this year. It is also developing a phage treatment for wound infections in partnership with the U.S. Army and hopes to begin testing it in humans this year as well.

Collins and others are also experimenting with phages, predatory viruses that infect and kill bacteria. Phages were used to treat bacterial infections in the early 20th century, before antibiotics were invented. But at that time there was no good way to identify which bacteria were causing an infection, and phages are highly selective, tuned to infect one specific type of bacterium. Because doctors could only guess which phage to use, treatments weren’t very effective. Phages were abandoned in the West, but remain popular in Eastern Europe, where cocktails of different phage species can still be bought over the counter.

Today, gene sequencing can quickly identify which bacterium is causing an infection, opening up new possibilities for phage therapy. But tests of phages in human patients have still been slow in coming. One small study in the United Kingdom five years ago hinted that phages might control chronic ear infections without side effects, but was never followed up with larger trials. Nestle Research Center conducted a study of phage therapy to treat diarrhea caused by Escherichia coli in children, but the study was terminated last fall, after a preliminary analysis of 120 patients revealed no benefit for the treatment.

Natural phages have some limitations: If injected directly into a person’s bloodstream, they tend to get sopped up by the liver and spleen before they can do their job. Because bacteria can quickly develop resistance to just one phage, the viruses should ideally be given in mixtures, which can be a challenge for industrial-scale production. The company AmpliPhi Biosciences has spent years figuring out how to produce large amounts of the right mixture of phage under high quality control standards. “We’ve figured out optimum time conditions and conditions for growing the phage,” said CEO Phil Young.

The company has developed an inhaled phage cocktail for drug-resistant Pseudomonas aeruginosa, a stubborn bacteria that infects the lungs of people with cystic fibrosis. The mix was successful in mice, and the company plans to launch a trial in humans this year. It is also developing a phage treatment for wound infections in partnership with the US Army, and hopes to begin testing it in humans this year as well.

Collins and others are also experimenting with phages, predatory viruses that infect and kill bacteria. Phages were used to treat bacterial infections in the early 20th century, before antibiotics were invented. But at that time there was no good way to identify which bacteria were causing an infection, and phages are highly selective, tuned to infect one specific type of bacterium. Because doctors could only guess which phage to use, treatments weren’t very effective. Phages were abandoned in the West, but remain popular in Eastern Europe, where cocktails of different phage species can still be bought over the counter.

Today, gene sequencing can quickly identify which bacterium is causing an infection, opening up new possibilities for phage therapy. But tests of phages in human patients have still been slow in coming. One small study in the United Kingdom five years ago hinted that phages might control chronic ear infections without side effects, but was never followed up with larger trials. Nestle Research Center conducted a study of phage therapy to treat diarrhea caused by Escherichia coli in children, but the study was terminated last fall, after a preliminary analysis of 120 patients revealed no benefit for the treatment.

Natural phages have some limitations: If injected directly into a person’s bloodstream, they tend to get sopped up by the liver and spleen before they can do their job. Because bacteria can quickly develop resistance to just one phage, the viruses should ideally be given in mixtures, which can be a challenge for industrial-scale production. The company AmpliPhi Biosciences has spent years figuring out how to produce large amounts of the right mixture of phage under high quality control standards. “We’ve figured out optimum time conditions and conditions for growing the phage,” said CEO Phil Young.

The company has developed an inhaled phage cocktail for drug-resistant Pseudomonas aeruginosa, a stubborn bacteria that infects the lungs of people with cystic fibrosis. The mix was successful in mice, and the company plans to launch a trial in humans this year. It is also developing a phage treatment for wound infections in partnership with the US Army, and hopes to begin testing it in humans this year as well.

New hope

Collins’ group is also engineering phages to carry different payloads, turning them into more effective weapons. One project modifies phages to kill bacterial cells without causing them to explode, which can trigger an immune response in the infected person. Another is designed to penetrate the slimy deposits called biofilms that bacteria produce in response to treatment with antibiotic drugs. This microbial goo forms on the surface of heart valves, artificial joints and catheters, protecting the cells against antibiotics and enabling persistent infections.

Collins’ phages carry genes that get integrated into the bacterium and force it to produce enzymes that break down biofilms, rendering it vulnerable to antibiotics. These phage products also work in mice, and a company called EnBiotix is now developing them for use in humans.

Because they are tailored to target one organism, these new precision bacteria-killing therapies will be more complicated to develop and produce than conventional drugs. And because they work in an entirely different way than antibiotic medicines, they may have difficulty getting approved by safety agencies like the Food and Drug Administration. For those reasons, major pharmaceutical companies have mostly stayed away from this research, leaving it to small biotechs and individual researchers like Collins. But that may change, if the planned clinical trials meet some success.

These inventions aren’t likely to replace antibiotics, Collins believes: “The master idea of these projects is to increase the effectiveness of the antibiotics we already have.” But by devising totally new ways of killing bad bugs, and minimizing collateral damage to beneficial bacteria, they show how the fight against drug-resistant bacteria might be once again tipped to our advantage.

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