Antibiotic-resistant bacteria are on the rise, but the pipeline for new drugs is drying up. Researchers are developing new strategies to avoid a resurgence of illnesses that once seemed easy to cure.
NEW WAYS OF FIGHTING BACTERIA
Four novel approaches to keep killers in check
I. Faecal transplants
They are not for the squeamish, but faecal transplants are a novel way to tackle bacterial infections.
Hospitals are seeing a growing problem of patients with severe diarrhoea caused by Clostridium difficile.
This bacterium is often present in low numbers in the gut of healthy people, but when they are treated with broad-spectrum antibiotics the good bacteria die off, allowing
C. difficile to take over.
Sometimes the only solution is a transplant of faeces from a screened donor, allowing good bacteria to recolonise the gut and outcompete C. difficile.
II. New targets
A common enzyme within many strains of bacteria called the ClpP protease plays a crucial role by cutting up various proteins to carry out important functions within the cell.
Researchers led by Stephan Sieber at Technische Universität München have found two sites within the enzyme that prevent it from working, along with a series of compounds that disrupt these two sites.
Stephan Sieber from TUM found two new targets against bacteria.
III. Slime cities
One thinks of bacteria as solitary organisms, unlike larger multicellular creatures, but in fact many human diseases arise when large groups of bacteria start cooperating.
In such communities, bacteria secrete substances that form a slimy “biofilm”, which helps them evade our immune system and resist antibiotics.
Søren Molin of the Technical University of Denmark is working on molecules that inhibit the growth of biofilms and has shown in particular that they develop in the airways of cystic fibrosis patients with pneumonia.
Søren Molin from DTU fights the growth of bacterial biofilms.
IV. Breaking the walls
Tuberculosis is a classic example of an infectious disease in which pharmaceutical companies have been reluctant to invest. Being most contagious among people who are malnourished and living in crowded conditions, it is more common in developing countries that cannot afford expensive drugs.
Yet progress is being made through EU funding of the MM4TB research consortium (More Medicines for TB). By screening existing libraries of compounds for anti-TB activity, the team has developed a new class of antibiotics called benzothiazinones, one of which, PBTZ169, is being tested in late-stage animal trials by École Polytechnique Fédérale de Lausanne (EPFL).
Promisingly, when the drug is used with existing antibiotics, it seems to work well against multi-drug-resistant strains of TB.
The compound works by weakening the bacterium’s cell wall. “The bacteria explode,” explains EPFL’s Stewart Cole.
Stewart Cole from EPFL has developed new drugs against tuberculosis.
Only two centuries ago, tuberculosis accounted for one in five deaths in Europe. There was no cure. To help limit contagion, the afflicted were often shut away, awaiting an unpleasant and lingering death.
Today a return of this “white plague” is not inconceivable. Strains of TB that are resistant to the most important antibiotics in our arsenal are now commonplace: more than 70,000 cases were reported in 2012 on the European continent.
Nor is tuberculosis the only resurging disease. More and more bacteria are becoming resistant to the drugs that have been developed to treat them – just as the pharmaceutical industry’s creation of new antibiotics is declining.
As a result, such common illnesses as pneumonia and stomach bugs could become untreatable. Standard medical procedures like hip replacements or chemotherapy could become too risky for fear of infections. Even minor wounds could trigger fatal blood poisoning.
“We’re going into a post-antibiotic age, where little scratches or splinters could kill you,” fears Mikael Lenz Strube, a biotechnologist at the Technical University of Denmark (DTU). “We need to figure out ways to deal with this – we don’t really have any choice.”
What are the options? For a start, supplies of antibiotics that still work should be husbanded carefully so as to slow the spread of resistance. That means doctors should prescribe them only when necessary, and patients should play their part by taking the full course of medicine exactly as prescribed. People taking sub-optimal doses are a major cause of resistance.
Then there is the other end of the drug pipeline. Pharmaceutical companies have been abandoning antibiotic research and development, seeing it as unprofitable. In 1990, 18 major drug firms were working in this area; by 2011 that number had dwindled to five.
The World Health Organization is now looking for ways to encourage the pharmaceutical industry to return to this field – for example, by paying firms directly for each new drug developed. Governments are also increasingly realising the importance of filling the R&D gap with publicly funded research. In addition, there is growing interest in entirely new strategies against bacterial infections.
Here are the five most promising approaches that go beyond traditional antibiotics.
1. Antibiotic boosters
Why go to the trouble of inventing novel antibiotics if you can breathe new life into some old ones? That is the idea behind a new drug class called “efflux inhibitors”, says Laura Piddock, a microbiologist at the University of Birmingham, who heads the UK’s Antibiotic Action group.
Bacteria often develop antibiotic resistance by pushing the drugs out of their cells with a molecular pump located in their membrane. Efflux inhibitors stop such pumps from working; if used alongside conventional antibiotics, they cause formerly resistant bacteria to become susceptible to the antibiotic again. “That’s a very promising area,” says Piddock.
2. Resistance-proof drugs
No matter how carefully antibiotics are used, the laws of evolution make resistance inevitable. In the presence of a drug that kills bacteria, any mutation that survives will have such an advantage that it quickly spreads through the population.
That’s why researchers are now interested in drugs that work through entirely different mechanisms. They do not kill bacteria, but merely make them less deadly. The hope is that such compounds will be resistance-proof.
Many disease-causing bacteria have dual personalities. When present in their human hosts in low numbers, they exist peaceably without doing any harm. But when their numbers are high enough they turn nasty, manufacturing a suite of compounds known as “virulence factors” that attack cells and undermine immune defences.
Such bacteria use special signalling molecules known as “quorum sensors” to detect when they have reached high enough numbers to mount an attack. Drugs that block these signalling molecules should stop bacteria from turning virulent – but since they do not kill the bacteria they should not trigger the evolution of resistance. Paul Williams of the University of Nottingham is developing agents that block the quorum-signalling molecules made by methicillin-resistant Staphylococcus aureus.
Some drugs would target other components of the virulence cascade. Researchers led by John Mekalanos of the Harvard Medical School have developed a compound called “virstatin”, which stops the cholera bacterium from making a key toxin.
3. Rewarding cheaters
Ask any economist: when any group of people work together to achieve a common goal, there are usually “cheaters”– individuals who try to derive the benefit without doing the work. Microbiologists have recently found that this applies to bacteria, too.
Manufacturing virulence factors is costly in terms of energy, so bacteria that ignore the signal to attack reap the benefits without paying the price. Such cheating has been observed in several kinds of disease-causing bacteria, including Pseudomonas aeruginosa, which causes pneumonia and wound infections in hospital patients.
Cheater bacteria outcompete virulent bacteria in the Petri dish, leading some researchers to believe that if they evolve during the course of a patient’s infection the balance can tip toward recovery. Steve Diggle, also at the University of Nottingham, is exploring whether the deliberate introduction of such bacteria into a patient could be similarly helpful.
4. Friendly bacteria
Most consumers are now familiar with the probiotic dairy foods that encourage “good bacteria” in our gut. The jury is still out on whether people should use these products routinely, but there is growing interest in their use by people taking a course of antibiotics, which kill off some of the normal gut flora.
The same principles may also be helpful in agriculture. Farmers used to routinely add low levels of antibiotics to animal feed, which caused their stock to add weight faster while reducing harmful infections. This practice has been phased out in Europe, since it encourages the development of resistant bacteria that could spread to people.
When the ban was imposed in 2006, pig farmers began to notice that more of their animals were getting diarrhoea caused by E. coli, especially straight after they were weaned. So there is interest in helping pigs fight off the E. coli by encouraging the growth of good bacteria in their guts instead.
While one strategy is to use probiotics – putting lactic acid bacteria in their feed – Mikael Lenz Strube believes it will be cheaper and more practical to instead use “prebiotics”, food substances that encourage existing lactic acid bacteria to multiply. His group at DTU is developing a prebiotic for pigs made from a waste product of potato starch manufacturing. “You can tailor it into something that the good bacteria like and the bad ones don’t like,” he explains.
5. Help from viruses
My enemy’s enemy is my friend, goes the saying, and that might apply to bacteria too. Their greatest enemies are “bacteriophages”, a large class of viruses that parasitise and kill bacteria, just as other viruses do the same to human cells.
Bacteriophages were discovered in the waters of the River Ganges in India more than 100 years ago. In the early 20th century they were used as treatment for bacterial infections, but interest diminished after antibiotics came on the scene. With the powers of antibiotics on the wane, U.S. biotech firms like Intralytix (Baltimore) and GangaGen (Palo Alto) have become interested in using phages as therapy. The advantage is that each virus attacks only one species of bacteria, instead of wiping out all the good bacteria in the gut. Phages also require fewer doses because they are self-breeding on encountering their target bacteria. Yet they are also self-limiting: once all the bacteria die, so do the phages.
On the other hand, bacteria can evolve resistance to phages, just as they do to antibiotics. That is not a reason to give up on them, says Piddock, but it does argue for the use of cocktails of several phages to make the development of resistance less likely. “They need to go through the same regulatory processes as other medicines,” says Piddock. “We need to ensure they are safe and that there are no unintended consequences.”
– By Louise Williams