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We Might Soon Have A New Way To Combat Antibiotic Resistance

Researchers may have found a new way to target and kill certain kinds of bacteria – but new drugs are still over a decade away.

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Bacteria are increasingly capable of resisting the drugs we use to kill them.

E. coli. By Credit: Rocky Mountain Laboratories, NIAID, NIH - NIAID. Public Domain / Via commons.wikimedia.org

It's a major problem. Antibiotic-resistant bacteria – "superbugs" – are on the rise, and we're not making any new antibiotics.

"I don't want to overstate the situation and say that all hell is breaking loose," Tim Jinks, a strategist at the biomedical charity the Wellcome Trust who studies drug-resistant infections, told BuzzFeed News. "But it is already a problem in some circumstances, and it's a problem we are soon to face very broadly."

Around 700,000 people die a year from drug-resistant infections, and a 2014 report for the British government predicted that by 2050, the number would rise to 10 million.

It's a problem of evolution. Using antibiotics kills almost all of the bacteria in a patient. But the ones that survive tend to the ones that are best able to resist those antibiotics.

Those hardy survivors then breed, and the next generation of bacteria are a bit more resistant to the antibiotic than the generation before it.

Methicillin-resistant Staphylococcus aureus (MRSA) is probably the most famous superbug, but drug-resistant strains of tuberculosis, gonorrhoea, E. coli, and others are all common. The Centers for Disease Control in the US have a list of the 18 biggest drug-resistant threats.

One kind of bacteria, "gram-negative" bacteria, is particularly hard to fight with antibiotics.

By Jeff Dahl - Own work, GFDL / Via commons.wikimedia.org

That's because they have a tough wall around the outside of their cell made of two membranes. That makes it much harder to create drugs that work against them, said Jinks: "The drugs have to pass through both these membranes. There are very few molecules which have the chemical properties that allow them to pass through but which still have a therapeutic effect."

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That's why there is cautious excitement about a study, published today, that seems to reveal an "Achilles heel" for these bacteria.

A beta-barrel protein, α-hemolysin, from the bacterium Staphylococcus aureus. By Bassophile at the English language Wikipedia, CC BY-SA 3.0 / Via commons.wikimedia.org

The study, which was carried out by British and Chinese scientists and published in the journal Nature, used a super-powerful light to examine the cell walls of gram-negative bacteria in atomic detail. It looked at how those walls are constructed and specifically at the "gates" in the walls that allow chemicals in and out.

Those gates are made of chemicals called beta-barrel proteins. There are five different proteins, and they link together to form a shape "a little bit like a top hat", Dr Joseph McPhee, a microbiologist at Ryerson University in Canada, told BuzzFeed News. One of the proteins, "beta-barrel assembly machinery A" (BAMA), forms the chimney of the top hat. The top of it pokes outside the cell wall.

The new study found that BAMA works as a channel and allows molecules to flow through the cell wall. Blocking the channel would kill the bacteria.

The research could lead to whole new classes of antibiotics, according to its authors.

Professor Changjiang Dong of the University of East Anglia, the lead author on the study, told BuzzFeed News that these proteins are "crucial" to the bacteria: "If we can break this cell wall [process], we can kill the gram-negative bacteria." And because one of the proteins is outside the cell wall, it means drugs that target it don't have to get through that wall first.

Dong said that "in a few years' time – less than 10 – we could create a compound that would kill the bacteria". Now that the structure of the beta-barrel proteins is known, he said, drugs can be made that attach to the shape of that protein and disrupt its working.

He also said that these new drugs would also be more difficult for bacteria to learn to fight off. Because the drugs attack the bacteria's defences, he said, the bugs will find it harder to develop resistance, although they may find a way eventually.

Other experts are optimistic about the study's findings, although they warn against getting too excited.

Methicillin-resistant Staphylococcus aureus. By National Institutes of Health (NIH) - National Institutes of Health (NIH), Public Domain / Via commons.wikimedia.org

Professor Colin Garner, the chief executive of the charity Antibiotic Research, told BuzzFeed News: "It is quite exciting. It could be a meaningful first step – they could identify new molecules which bind to [the beta-barrel protein], and if they do that, cell wall synthesis would stop and the bacteria would die."

But, he said, "it's a long way to go, from these very fundamental studies on the composition of bacterial cell walls and proteins to getting a drug which could be used in the clinic".

He was very sceptical about the idea that drugs could be available within 10 years. "I'd be very surprised if it could happen in less than 10 years," he said. "Normally one is talking 10 to 20 years to get something useful, and at massive costs. A billion dollars, or a billion and a half, are the figures often quoted." Jinks agreed, saying 15 years would be a good estimate.

Garner also warned that it was far too early to say whether any new drugs would be more difficult for bacteria to develop resistance to. "I think that's a very big claim," he said. "People have said similar things about antibiotics in the past, but bacteria are very smart and they find ways around it."

It's particularly interesting, one scientist said, because it's a new way of looking at the problem.

"This isn't the old-fashioned 'grow bugs and see what kills them' approach," Dr Colin Davidson, a biotechnology researcher at Cambridge University, told BuzzFeed News. "It's the first step towards maybe finding new families of drugs.

"Cell wall proteins are really hard to study, because they're not easy to crystallise and purify. So any deeper understanding that comes from this kind of imaging really does give us clues to how we might design new drugs targeting these proteins." He agreed, though, that new drugs were "a decade or more" away.

There are huge obstacles to overcome in developing any drugs.

Garner pointed out that the BAMA protein is also present in human cells. Mitochondria, the little energy-producing organelles inside each of our cells, are all descended from bacteria. "We have to be sure that our mitochondria wouldn't be damaged [by a drug targeting BAMA], that only the bacterial cells are," he said. "Otherwise there's a possibility that the drug would be toxic to humans."

Also, the researchers have only looked at one species of bacterium, E. coli. "There are at least four species of gram-negative bacteria that cause problems," Garner said. "They haven't shown that those other ones have the same complex in their cell walls." If they don't, though, he says, this could still lead to antibiotics targeted very precisely at E. coli, which would be important in itself.

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And as exciting as it could be, even if new drugs are developed, it will just be kicking the problem down the road if the way we create and use antibiotics isn't radically changed.

"It's not that we have a single problem," said Jinks. "There are multiple problems that, together, create what is threatening to be a crisis."

One problem is that we've stopped making new antibiotics.

Antibiotic Research / Via antibioticresearch.org.uk

No new antibiotics have been developed since the early 2000s, and before the two that were invented then, none since the 1970s.

That's partly because it's difficult to make new antibiotics, but it's also because the economic incentives just aren't there for pharmaceutical companies. Patients take blood pressure drugs or diabetes drugs every day for their lives. But antibiotic drugs are only taken for a week or so, and ideally should be used as little as possible so that bacteria don't get the chance to develop resistance to them.

The UEA study shows an interesting way that new drugs could be made, but, Jinks said, "bluntly, it does not change the economic outlook at all. The economic models are so dysfunctional that there needs to be new structures to make the business prospects more favourable."

He thinks governments need to work more with private companies to solve the problem. Garner, whose charity Antibiotic Research is the first one in the world dedicated to the problem of antibacterial resistance, argues that the charitable sector can help too.

And another problem is that we're using the antibiotics we do have in profligate and dangerous ways.

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"We need to consider how we use this arsenal of medicines effectively," said Jinks. Antibiotics are sometimes used inappropriately in livestock, which reduces their effectiveness in humans, because many bacteria can infect both us and animals. And even more damagingly, doctors often prescribe antibiotics to patients when they're not needed.

That's partly because of the difficulties of diagnosing an infection accurately. If a doctor isn't sure whether a patient has a bacterial infection, they often, reasonably, prescribe antibiotics. "To be fair to both patients and clinicians, it's better to be safe than sorry," Jinks said. New, improved diagnostic techniques will help stop that.

One way people can help fight against drug-resistant bacteria is to make sure they know what antibiotics can and can't do.

Many people don't understand what antibiotics are for, or that they only work on certain diseases, so they demand them for illnesses even when they'll do no good. "People will need to better understand the risks of using antibiotics," said Jinks.

That's starting to happen, he said, but "we've gone through an era which has taken these medicines for granted, and we need to make sure that these limited resources are treated with care".

Tom Chivers is a science writer for BuzzFeed and is based in London.

Contact Tom Chivers at tom.chivers@buzzfeed.com.

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