As antibiotics have become more common, so too have bacteria that are immune to their effects. Bill Condie explains why, and talks to CO-ADD scientists building the weapons for the next phase of this arms race.

A superbug is usually defined as a microorganism that’s resistant to commonly used antibiotics - but not all superbugs are created equal.

The number of different antibiotics to which it can be resistant determines the degree of the superbug. Some are resistant to one or two, but others can be resistant to multiple drugs.

So, if they are resistant to every available antibiotic, they would be the superbug of all superbugs.

Cases where people are dying from antibiotic-resistant infections are still comparatively rare, particularly in places like Australia, which doesn’t allow antibiotics to be available over the counter.

But around the world, there are increasing numbers of people dying because their infection can’t be treated by any available antibiotic.

Currently, antibiotic-resistant bacteria cause 700,000 deaths worldwide each year, and a UK government review on antimicrobial resistance predicted this number could increase to 10 million by 2050.

If superbugs are allowed to spread, we may reach a point where it is too dangerous to conduct surgeries such as c-sections and transplants because of the risk of superbug infection, which would have huge implications for the health of people around the world.

Gram negative vs Gram positive bacteria – what’s the difference?

There are two major classes of bacteria known as Gram positive and Gram negative. They take their names from how they respond to the Gram staining test, which in turn was named after Danish scientist Hans Christian Gram, who developed the technique.

A bacterium is known to be Gram negative or Gram positive based on its reaction to the test – Gram positive bacteria stain purple, and Gram negative do not.

Gram negative bacteria are generally considered the more difficult to treat. They include such nasties as E. coli; Salmonella; Pseudomonas; and the Gonococcus bacteria - responsible for the sexually transmitted infection gonorrhoea.

Antibiotics have a tough time dealing with Gram negative bacteria because of their additional outer membrane, which prevents drugs from getting inside. And if the drugs do manage to get in there, the bacteria have a pumping mechanism that forces them back out again so quickly, they don’t have time to work.

Gram negative bacterial infections concern doctors and researchers because there are fewer drugs to treat them and - more worryingly - fewer in the pipeline to deal with them in the future.

But that’s not to say that Gram positive infections aren’t of serious concern, too.

While they are easier to treat, and there are many more drugs available to combat them, there are also many, many times the numbers of drug-resistant infections from Gram positive bacteria compared with Gram negative.

These include the superbug Methicillin-resistant Staphylococcus aureus – better known by its acronym MRSA. Dr Mark Blaskovich, a senior research chemist at the Institute for Molecular Bioscience (IMB) at The University of Queensland in Australia, describes MRSA as the “poster child” of Gram positive superbugs.

But he adds that multi-drug resistant strep pneumonia is a growing concern as well.

Blaskovich points to a report from the Centers for Disease Control (CDC) in the US from 2013, which counted the number of infections and the number of deaths from different types of drug-resistant bacteria.

The number of infections from drug-resistant Gram positive MRSA or strep pneumonia were over a million, versus 30,000 or so from Gram negative bacterial infections.

And drug-resistant Gram positive bacteria were by far the biggest killers in the report, too. The number of deaths from resistant bacteria were about five-fold higher for Gram positive compared to Gram negative infections.

How did this happen? Why have superbugs spread so far?

In some respects, we are suffering from too much of a good thing. There’s no doubt that we have misused modern antibiotics since they were first developed in the 1940s. Globally, the major cause of drug resistance is the overuse of the drugs.

And it’s not confined to developing countries. India and some Asian countries suffer the most from antibiotic-resistant strains, but other nations such as Brazil, Greece, and South Africa have serious problems, as well.

It’s no coincidence that these countries are also lax on controlling the use of antibiotics. There are strong correlations with those countries where antibiotics are available over the counter for people to take whenever they want and the incidence of high levels of resistant bacteria.

But that doesn’t let countries with more stringent regulations, such as Australia, Canada, and the UK, off the hook.

“Probably two-thirds of antibiotics are inappropriately prescribed,” Dr Blaskovich said. “Doctors will prescribe them when a patient has the flu or a cold and is demanding something, or the doctor feels they have to give something. There is a lot of mis-prescription of antibiotics when they aren’t really needed.”

While hospitals have traditionally been the breeding ground of the most serious infections (that’s where MRSA got its start), superbug infections are increasingly being acquired within the community.

Once they’re out in the open, people can easily spread them. And with global travel to assist the spread, nowhere is safe.

“While they might not get an actual infection at the time, they start carrying these bacteria and will bring back the resistant strains with them,” Dr Blaskovich explained.

“So even though a traveller may not be sick at the time, at some point those bacteria are still colonised on the body and if they get a cut then those resistant bacteria have the opportunity to cause an infection.”

The other major misuse is in agriculture. Globally about 70 per cent of antibiotics are used for animals, not people. Mostly that’s not for therapeutic treatment of a sick animal, it’s either as a prophylactic against disease or as a growth promoter.

So what can we do to turn back the tide?

Tougher policies on prescribing would be a relatively simple way to help, as would controls on the agricultural use of antibiotics. That would take some of the pressure off existing antibiotics that are yet to meet resistance.

Meanwhile, researchers are pursuing a range of approaches. Some are looking for new antibiotics or ‘enhanced’ versions of the ones already in use – super-drugs for super-bugs.

Others are working on diagnostic improvements in order to react faster to an infection, understand its resistance profile better, and target it more effectively.

Another option is to look back through the research literature to find older antibiotics that were overlooked when they first discovered.

Researchers such as Professor Matt Sweet, Director of the IMB’s Centre for Inflammation & Disease Research, are focussed on the immune system. He’s trying to understand how it detects and responds to infections, to come up with treatments that don’t require any antibiotics at all.

“We are trying to manipulate or ‘train’ the immune system to better defend against infection,” Professor Sweet said. “This is essentially what vaccines do, and it’s very successful for many pathogens.”

This has led him to investigate macrophages, which he describes as the ‘garbage trucks’ of our bodies, whose role is to gobble up pathogens.

Time to talk strategy

Researchers in the Centre for Superbug Solutions at IMB are pursuing several different options in a bid to take the upper hand in the fight against superbugs. One of them is rapid diagnostics.

In some ways, diagnosing an infection today has moved on very little since 100 years ago. First, you have to make an initial culture of the bacteria and let it grow for 24 hours to get enough bacteria to apply some of the more modern techniques.

The you might have to wait another 24 or 36 hours to confirm what type of bacterium it is and the antibiotics to which it’s resistant.

If doctors could quickly confirm that an infection was caused by bacteria (and not a virus), and identify the type of bacteria and its resistance profile, they could determine the correct antibiotic to use immediately. So IMB researchers are working on a technique to capture bacteria selectively in a blood test or some other biological sample, and concentrate it within an hour or two.

“Now you have a clean captured sample that you can apply techniques to determine what the bacteria is,” Dr Blaskovich said.

One of the techniques they’re applying to that is whole genome nanopore sequencing - high-tech sequencing that provides real-time information. So rather than having to chop up the DNA and run it through a massive machine that takes hours, this technique strings the DNA through a tiny pore and gives a read of the whole sequence as it passes through.

The sequencing for bacteria happens in real time, so if everything could be integrated within 3 hours of getting a sample, you could tell what type of bacteria you have, and a few hours later, what sort of resistance profile it could have.

On the therapeutic side, IMB researchers have a number of different projects. The most advanced is their Gram positive program.

In this, they’re using the glycopeptide antibiotic Vancomycin as a core, and adding peptide groups to it in order to make a ‘super-vancomycin’ that more selectively targets bacterial cells.

These groups are designed to interact selectively with the bacterial cell instead of a mammalian cell, in a bid to increase their potency at killing bacteria while also reducing the unwanted side effects they have on human cells.

The researchers are also looking back to the so-called golden age of antibiotics in the 1950s and 1960s, when most antibiotics were discovered.

Most were produced using natural products – other bacteria, fungi, or plants. Many of these antibiotics were reported in the research literature, but because there were so many choices, most weren’t developed any further at the time.

Already the search appears to have borne fruit, including a lipopeptide antibiotic that targets highly drug-resistant Gram negative bacteria. This class of lipopeptides is related to antibiotics that are currently the ‘last resort’, such as colistin and polymyxin.

The problem with these is that they’re operating at the extremes – just below the toxic level for humans – so dosages can’t be increased. The new antibiotics work against bacteria that are resistant to these ‘last resort’ antibiotics, and appear to be safer.

The IMB is also involved in a global initiative to try to uncover new chemical diversity that has antibiotic activity.

 The Community for Open Antimicrobial Drug Discovery (CO-ADD) is a not-for-profit initiative funded by over $5 million from the Wellcome Trust. The initiative invites chemists from around the world to submit their compounds for free screening for antimicrobial activity.

In less than three years, over 200 groups from 40 countries have sent in more than 200,000 samples for testing, with thousands of active compounds identified. All results will be published in an online database accessible to the global community of antibiotic researchers, providing an invaluable resource.