Superbugs have an arsenal of defences — but we’ve found a new way around them



Superbug Acinetobacter baumannii captured by an electron microscope.
Janice Carr/Centers for Disease Control and Prevention

Fernando Gordillo-Altamirano, Monash University and Jeremy J. Barr, Monash University

Researchers have not discovered any new antibiotics in decades. But our new research, published today in Nature Microbiology, has found a way to give a second wind to the antibiotics we do have.

It involves the use of viruses that kill bacteria.

The problem

Hospitals are scary, and the longer you remain in them, the greater your risk. Among these risks, hospital-acquired infections are probably the biggest. Each year in Australia, 180,000 patients suffer infections that prolong their hospital stays, increase costs, and sadly, increase the risk of death.

It sounds absurd — hospitals are supposed to be the cleanest of places. But bacteria are everywhere and can adapt to the harshest of environments. In hospitals, our increased use of disinfectants and antibiotics has forced these bacteria to evolve to survive. These survivors are called “superbugs”, with an arsenal of tools to resist antibiotics. Superbugs prey on the most vulnerable patients, such as those in intensive care units.

Acinetobacter baumannii is a superbug responsible for up to 20% of infections in intensive care units. It attaches to medical devices such as ventilator tubes and urinary and intravenous catheters. It causes devastating infections in the lungs, urinary tract, wounds and bloodstream.

Treatment is difficult because A. baumannii can produce enzymes that destroy entire families of antibiotics. Other antibiotics never make it past its outer layer, or capsule. This outer layer — thick, sticky, viscous and made of sugars — also protects the superbug from the body’s immune system. In some cases, not even the strongest — and most toxic — antibiotics can kill A. baumannii. As a result, the World Health Organisation named it a critical priority for the discovery of new treatments.




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A (somewhat) new solution

It’s said that the enemy of your enemy is your friend. Do bacteria have enemies?

Bacteriophages (or phages, for short) are the natural predators of bacteria. Their name literally means “bacteria eater”. You can find phages wherever you can find bacteria.

Phages are viruses. But don’t let that scare you. Unlike famous viruses — such as HIV, smallpox or SARS-CoV-2, the coronavirus that causes COVID — phages cannot harm humans. They only infect and kill bacteria. In fact, phages are quite picky. A single phage normally infects only one type of bacteria.

Electron micrograph image of multiple bacteriophages attached to a bacterial cell wall
Phages attach to the outside of bacteria, initiating the killing process.
Dr Graham Beards/Wikimedia Commons, CC BY-SA

Since their discovery in the early 1900s, doctors thought of an obvious use for phages: treating bacterial infections. But this practice, known as phage therapy, was largely dismissed after the discovery of antibiotics in the 1940s.

Now, with the alarming rise of antibiotic-resistant superbugs, and a lack of new antibiotics, researchers are revisiting phage therapy. In Australia, for example, a team lead by Professor Jon Iredell at Sydney’s Westmead Hospital reported in February the safe use of phage therapy in 13 patients suffering from infections by another superbug, Staphylococcus aureus.

We began our study by “hunting” for phages against A. baumannii. From waste water samples sourced from all over Australia, we successfully isolated a range of phages capable of killing the superbug. That was the easy part.

Erasing antibiotic-resistance

When mixing our phages with A. baumannii in the laboratory, they were able to wipe out almost the entire bacterial population. But “almost” was not good enough. Within a few hours, the superbug showed how wickedly smart it is. It had found a way to become resistant to the phages and was happily growing in their presence.

We decided to take a closer look at these phage-resistant A. baumannii. Understanding how it outsmarted the phages might help us choose our next attack.

We discovered that phage-resistant A. baumannii was missing its outer layer. The genes responsible for producing the capsule had mutated. Under the microscope, the superbug looked naked, with no sign of its characteristic thick, sticky and viscous surface.

To kill their bacterial prey, phages first need to attach to it. They do this by recognising a receptor on the surface of the bacteria. Think of it as a lock-and-key mechanism. Each phage has a unique key, that will only open the specific lock displayed by certain bacteria.

Our phages needed A. baumannii‘s capsule for attachment. It was their prospective port of entry into the superbug. When attacked by our phages, A. baumannii escaped by letting go of its capsule. As expected, this helped us decide our next attack: antibiotics.

We tested the action of nine different antibiotics on the phage-resistant A. baumannii. Without the protective capsule, the superbug completely lost its resistance to three antibiotics, reducing the dosage needed to kill the superbug. Phages had pushed the superbug into a corner.

We established a way to revert antibiotic-resistance in one of the most dangerous superbugs.

Looking forward

Phage therapy has already been used in patients with life-threatening A. baumannii infections, with successful results. This study highlights the possibility of using phages to rescue antibiotics, and to use them in combination. After all, two is better than one.The Conversation

Fernando Gordillo-Altamirano, Medical Doctor, PhD Student, School of Biological Sciences, Monash University and Jeremy J. Barr, Senior Lecturer in School of Biological Sciences, Microbiology, Monash University

This article is republished from The Conversation under a Creative Commons license. Read the original article.

OM85: could bacteria in a capsule protect us from coronavirus and other respiratory infections?



Shutterstock

Peter Sly, The University of Queensland

Scientists around the world are continuing to test countless vaccines and drugs in the hope of finding effective ways to prevent and treat COVID-19.

Among the trials happening in Australia is one my team is about to begin, looking at something called OM85.

OM85 is not a conventional drug, but a combination of molecules extracted from the walls of bacteria that commonly cause respiratory infections.

It’s not available in Australia, but has been used widely in Europe and South America for 40-50 years, commonly under the brand name Broncho-Vaxom.

We’re now looking at its potential to prevent respiratory infections, including COVID-19. But how does it work?




Read more:
Where are we at with developing a vaccine for coronavirus?


First, a bit of background

Some of our organs, including the skin, airways and lungs, and gastrointestinal tract, are effectively “open” to the outside world. The cells that line these organs, called mucosal linings, host trillions of bacteria.

These bacteria, known as our “microbiota”, play essential roles in keeping us healthy. This is especially important in the gastrointestinal tract, where the microbiota “train” the immune system.

One of the ways they do this is by providing a continuous stream of signals that move through mucosal linings into the tissues below, where immune cells are found. Specialised immune cells responsible for detecting the invasion of infectious pathogens recognise and respond to these signals.

We now recognise these signals from the microbiota operate as “immune training” agents, helping to keep the front-line defences of the immune system in a state of high alert.

OM85 is made from molecules extracted from the walls of bacteria.
Shutterstock

OM85 is an immune stimulant

OM85 appears to enhance some important aspects of this natural “immune training” process. One way it does this is by stimulating the maturation of regulatory T-cells (called Tregs) in the lymph glands in the upper intestine.

Once they have fully matured, these Tregs can migrate to other mucosal surfaces in the body to bolster local anti-inflammatory defences. This process is especially important in the lungs and airways to prevent respiratory infections.




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Explainer: what is the gut microbiota and how does it affect mind and body?


OM85 signals also leak into our circulation. There they are recognised by cells in the bone marrow, which control the production of other immune cell types.

This results in increased immune cells – both in number and function – that travel to front-line mucosal surfaces, including the airways, to further bolster our immune defences.

We strongly suspect OM85 also influences the makeup of the gastrointestinal microbiome itself, although we know very little about how this happens. This in turn helps to promote the survival of bacterial strains that stimulate the immune system.

What the evidence tells us

OM85 is a preventative, given to those at risk of more severe consequences from respiratory infections, rather than as a treatment of current infections.

Studies have shown OM85 reduces the risk of wheeze linked to infection in infants and schoolchildren.

It also reduces the incidence of
severe flare-ups of chronic obstructive pulmonary disease in adults.

A review of 35 placebo-controlled studies involving 4,060 children concluded that immune stimulants, including OM85, reduced respiratory infections by an average of 40% in susceptible children.




Read more:
A strong immune system helps ward off colds and flus, but it’s not the only factor


OM85 has a good safety profile. A small proportion of people may experience some gastro-intestinal upset, but in clinical trials, such as one we conducted in infants, side effects are rarely seen.

So why don’t we use it more widely?

No application has been made to bring OM85 to Australia. We are a small market not necessarily attractive to drug manufacturers.

In countries where OM85 is available, doctors can prescribe it but people can also buy it over the counter, in the same way they might a complementary medicine or health food supplement.

Research shows OM85 can reduce the risk of severe respiratory infections in children.
Shutterstock

OM85 has attracted plenty of scepticism in its time, with some people regarding it as “snake oil”.

Scientists are sceptical when we don’t understand why something works, or at least where we don’t have a plausible explanation for how it works. The idea something swallowed but not absorbed could protect the lungs sounds fanciful, especially without solid explanations.

But as we start to understand more about the mechanisms that may explain how OM85 works in the body, and with the accumulating clinical evidence, we have good reason to be open to and further explore its potential.

What we’ll do in the trial

Health-care workers are susceptible to severe respiratory respiratory infections associated with other viruses, including influenza, that can cause them to miss work.

We plan to give 1,000 health-care workers OM85, half immediately and half delayed by three months.

To understand how OM85 works we will collect blood samples and test immune responses.

We will determine which virus caused the respiratory illnesses if illness occurs (COVID-19 or other), whether the immune response is different depending on the virus, and whether OM85 is equally effective against all respiratory viruses encountered.

The trial is due to start this month and first results should be available by November.




Read more:
The fascinating history of clinical trials


The Conversation


Peter Sly, Director, Children’s Health and Environment Program and World Health Organization Collaborating Centre for Children’s Health and Environment, The University of Queensland

This article is republished from The Conversation under a Creative Commons license. Read the original article.

We’ve discovered how these deadly bacteria use a common sugar to spread through the body. It could help us stop them



CDC/Antibiotic Resistance Coordination and Strategy Unit. Medical Illustrator: Meredith Newlove

Vikrant Minhas, University of Adelaide

Although bacteria are single-celled and microscopically small, they still need energy to survive, just like us. One of the most efficient ways of acquiring energy for bacteria is through sweet, soluble carbohydrates: sugars.

In fact, the keen ability of the deadly bacteria Streptococcus pneumoniae to use the plant-derived sugar raffinose may explain how it spreads through the human body.

S. pneumoniae is a bacteria that can quickly develop antibiotic resistance. Each year it causes millions of infections and about one million deaths. Its “ecological niche”, which refers to the natural position of a species within an ecosystem, is our noses and throats, where it doesn’t cause disease.

But from there, S. pneumoniae can spread into the lungs, blood and brain, or more locally into the ear, to cause diseases such as pneumonia, bacteremia, meningitis and otitis media (middle ear inflammation).

Unfortunately, S. pneumoniae is a genetically diverse pathogen, which means it has many different strains. This complicates research efforts to identify how the bacteria spreads into specific sites of the body.

New research published today in Nature Communications Biology by my colleagues and I circumvented these genetic diversity issues by studying closely related strains of S. pneumoniae. We discovered a difference in a gene between two bacterial strains that regulated their use of raffinose, and this resulted in one being more likely to spread and cause disease.




Read more:
Scientists still searching for causes of mysterious pneumonia outbreak in China


Sickly sweet, sugars and bacterial disease

In our previous research, two closely related strains of S. pneumoniae were isolated, one from the blood of a patient and another from the ear. Their sequenced genomes were aligned to pick out differences that may impact how they spread to different parts of the body, and hence how they cause disease.

We found a difference in the regulating gene rafR which is responsible for raffinose uptake. This difference allowed the bacteria in the blood sample to use raffinose more efficiently than in the ear sample.

When infecting mice lungs with S. pneumoniae through their nose, we found the blood sample remained in the lungs, causing invasive disease. However, the ear sample was cleared from the lungs, and was unable to cause disease.

Remarkably, swapping the rafR gene between the strains switched their ability to use raffinose, and the way the disease progressed in each case reversed too. This confirmed the rafR gene was indeed playing a large role in causing disease.

Streptococcus pneumoniae imaged with a scanning electron microscope. This bacteria is a major cause of pneumonia. When present in the nose or throat (its ‘ecological niche’) it benefits from the human body without harming it.
Debbie Marshall, CC BY-SA

In our most recent work, we wanted to figure out how this sugar-regulating gene was so profoundly impacting disease progression.

Using a cutting-edge sequencing technique during live mice infections, we discovered the difference in the rafR gene altered how both the mice and the bacteria responded to infection. Notably, strains containing the rafR from the ear sample resulted in more neutrophils, an important immune cell, at the site of infection.

In experiments where neutrophils were depleted in the lungs, the ear sample was not cleared, and the risk of disease was more. This research highlights how this single difference in the gene increased neutrophil levels during infection, preventing S. pneumoniae from causing invasive disease.

Potential research impacts

Raffinose is mainly found in vegetables, grains and legumes. It’s not known whether the human body ever has high enough levels of it to dramatically impact the likelihood of disease. It may be a carbohydrate similar in structure to raffinose is activating the raffinose regulator rafR instead.

Nonetheless, our research provides insight into how S. pneumoniae causes disease. As we understand what enables this deadly bacteria’s spread through the body, more paths will open up to stopping it.

If this raffinose phenomenon proves to be widespread across S. pneumoniae strains, blocking their ability to use raffinose may prevent them from surviving in, and thus invading, the lungs.

This illustration depicts a gram stained specimen under a microscope, with a number of Streptococcus pneumoniae bacteria (the small black dashes).
CDC

Treatments that prevent S. pneumoniae from spreading around the body may be better for preventing disease compared to simply inhibiting or killing the bacteria, as is current practice.

S. pneumoniae can stay in our nose and throats, where it does not cause disease. It plays an import role in this ecosystem. When this bacteria is killed, other deadly bacteria may take its place and spread to sites such as the lungs to cause disease.

The risk in failing to find new treatments

S. pneumoniae’s ability to rapidly develop antibiotic resistance has led the World Health Organisation and US Centres for Disease Control and Prevention to list it as a priority pathogen.

Though vaccines are available, they’re far from perfect and fail to cover all the different strains of S. pneumoniae. If new treatments and vaccines aren’t created soon, the already deadly impact of this bacteria may increase.

Despite the known dangers, research into discovering new antibiotics has been slow. Many treatments in the pipeline don’t provide much benefit over existing antibiotics. Also, effective new treatments usually aren’t implemented widely, and are instead used as a back up in case all else fails. This greatly reduces their profitability, which in turn decreases incentives to make them.

In a worst case scenario, antibiotic-resistant bacteria could kill up to ten million people each year by 2050. To avoid such catastrophe, more research is needed on how bacteria cause disease. And with this knowledge we may be able to lessen the likelihood of future pandemics.




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The Conversation


Vikrant Minhas, PhD candidate, University of Adelaide

This article is republished from The Conversation under a Creative Commons license. Read the original article.

‘Deeply worrying’: 92% of Australians don’t know the difference between viral and bacterial infections


Paul De Barro, CSIRO

We are four months into a global virus outbreak, and public health awareness could well be at an all-time high. Which is why it is astonishing to discover that 92% of Australians don’t know the difference between a viral infection and a bacterial one.

The statistic comes from a survey carried out by CSIRO in March to inform our work on the OUTBREAK project – a multi-agency mission aimed at preventing outbreaks of antibiotic-resistant bacterial infections.

Our survey of 2,217 people highlights a disturbing lack of knowledge about germs and antibiotics. It reveals 13% of Australians wrongly believe COVID-19, a viral disease, can be treated with antibiotics, which target bacteria.




Read more:
Why are there so many drugs to kill bacteria, but so few to tackle viruses?


More than a third of respondents thought antibiotics would fix the ‘flu or a sore throat, while 15% assumed antibiotics were effective against chicken pox or diarrhoea.

While 25% of those surveyed had never heard of antibiotic resistance, 40% admitted having taken antibiotics that didn’t clear up an infection. And 14% had taken antibiotics as a precaution before travelling overseas, despite this being unnecessary and ineffective for warding off holiday ailments.

Fuelling the rise of superbugs

The results are deeply worrying, because people who do not understand how antibiotics work are more likely to misuse or overuse them. This in turn fuels the rise of drug-resistant bacteria (also known as “superbugs”) and life-threatening infections.

While COVID-19 has brought the economy to its knees, superbugs pose economic challenges too. Australian hospitals already spend more than A$11 million a year treating just two of the most threatening drug-resistant infections, ceftriaxone-resistant E. coli and methicillin-resistant MRSA.

Without effective antibiotics, thousands more people will die from sepsis and people will be sicker for longer, slashing the size of the workforce and productivity. By 2050, drug-resistant bacteria are forecast to cost the nation at least A$283 billion and kill more people than cancer.




Read more:
Explainer: what are superbugs and how can we control them?


One crucial way to stop this is to improve public understanding of the value of antibiotics. Antibiotics that lose their effectiveness are very difficult to replace, so they need to be treated with respect.

Almost all today’s antibiotics were developed decades ago and, of the 42 antibiotics under development worldwide, only five are considered truly new, and only one targets bacteria of greatest drug-resistance concern.

No time to waste

We don’t know the full impact of drug-resistant bacteria in Australia. With about 75% of emerging infectious diseases coming from animals, there is no time to waste in getting a better understanding of how superbugs are spreading between humans, the environment and animals. That’s where the OUTBREAK project comes in.

This network, led by the University of Technology Sydney, uses artificial intelligence to analyse an immense amount of human, animal and environmental data, creating a nationwide system that can predict antibiotic-resistant infections in real time. It maps and models responses and provides important information to doctors, councils, farmers, vets, water authorities, and other stakeholders.

OUTBREAK offers Australia a unique opportunity to get on the front foot against superbugs. It would save millions of lives and billions of dollars, and could even be scaled globally.

Alongside this high-tech response, we need Australians to get to know their germs, and stop taking antibiotics unnecessarily. Without antibiotics, we may find ourselves facing a host of new incurable diseases, even as the world grapples with COVID-19.The Conversation

Paul De Barro, Senior Principal Research Scientist, Ecosystem Sciences, CSIRO

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Why are there so many drugs to kill bacteria, but so few to tackle viruses?



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Christine Carson, University of Western Australia and Rachel Roper, East Carolina University

As the end of the second world war neared, mass production of the newly developed antibiotic penicillin enabled life-saving treatment of bacterial infections in wounded soldiers. Since then, penicillin and many other antibiotics have successfully treated a wide variety of bacterial infections.

But antibiotics don’t work against viruses; antivirals do. Since the outbreak of the coronavirus pandemic, researchers and drug companies have struggled to find an antiviral that can treat SARS-CoV-2, the virus that causes COVID-19.




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Why are there so few antivirals? The answer boils down to biology, and specifically the fact viruses use our own cells to multiply. This makes it hard to kill viruses without killing our own cells in the process.

Exploit our differences with bacteria

The differences between bacterial and human cells are what make antibiotics possible.

Bacteria are self-contained life forms that can live independently without a host organism. They are similar to our cells, but also have many features not found in humans.

For example, penicillin is effective because it interferes with the construction of the bacterial cell wall. Cell walls are made of a polymer called peptidoglycan. Human cells don’t have a cell wall or any peptidoglycan. So antibiotics that prevent bacteria from making peptidoglycan can inhibit bacteria without harming the human taking the medicine. This principle is known as selective toxicity.

Viruses use our own cells to replicate

Unlike bacteria, viruses cannot replicate independently outside a host cell. There is a debate over whether they are really living organisms at all.

To replicate, viruses enter a host cell and hijack its machinery. Once inside, some viruses lie dormant, some replicate slowly and leak from cells over a prolonged period, and others make so many copies that the host cell bursts and dies. The newly replicated virus particles then disperse and infect new host cells.

An antiviral treatment that intervenes in the viral “life” cycle during these events could be successful. The problem is that if it targets a replication process that is also important to the host cell, it is likely to be toxic to the human host as well.

Killing viruses is easy. Keeping host cells alive while you do it is the hard part.




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In the fight against coronavirus, antivirals are as important as a vaccine. Here’s where the science is up to


Successful antivirals target and disrupt a process or structure unique to the virus, thereby preventing viral replication while minimising harm to the patient. The more dependent the virus is on the host cell, the fewer targets there are to hit with an antiviral. Unfortunately, most viruses offer few points of unique difference that can be targeted.

Another complication is that different viruses vary from each other much more than different bacteria do. Bacteria all have double-stranded DNA genomes and replicate independently by growing larger and then splitting into two, similar to human cells.

But there is extreme diversity between different viruses. Some have DNA genomes while others have RNA genomes, and some are single-stranded while others are double-stranded. This makes it practically impossible to create a broad spectrum antiviral drug that will work across different virus types.

Antiviral success stories

Nevertheless, points of difference between humans and viruses do exist, and their exploitation has led to some success. One example is influenza A, which is one form of the flu.

Influenza A tricks human cells so it can enter them. Once inside our cells, the virus needs to “undress”, removing its outer coat to release its RNA into the cell.

A viral protein called matrix-2 protein is key to this process, facilitating a series of events that releases the viral RNA from the virus particle. Once the viral RNA is released inside the host cell, it is transported to the cell nucleus to start viral replication.

But if a drug jams the matrix-2 protein, the viral RNA can’t exit the virus particle to get to the cell nucleus, where it needs to be to replicate. So, the infection stalls. Amantadine and rimantadine were early antiviral successes targeting the matrix-2 protein.

Zanamivir (Relenza) and oseltamivir (Tamiflu) are newer drugs that have also had success in treating patients infected with influenza A or B. They work by blocking a key viral enzyme, obstructing virus release from the cell, slowing the spread of infection within the body, and minimising the damage the infection causes.

We need to find what makes SARS-CoV-2 unique

A COVID-19 vaccine may be difficult to create. So testing antivirals to find one that can effectively treat COVID-19 remains an important goal.

Much depends on knowing the intricacies of the SARS-CoV-2 virus and its interactions with human cells. If researchers can identify unique elements in how it survives and replicates, we can exploit these points of weakness and make an effective antiviral treatment.




Read more:
Where are we at with developing a vaccine for coronavirus?


This article is supported by the Judith Neilson Institute for Journalism and Ideas.The Conversation

Christine Carson, Senior Research Fellow, School of Biomedical Sciences, University of Western Australia and Rachel Roper, Associate Professor of Microbiology and Immunology, East Carolina University

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Antibiotic resistance is not new – it existed long before people used drugs to kill bacteria



Antibiotic resistance can spread between microbes within hours.
Lightspring/Shutterstock.com

Ivan Erill, University of Maryland, Baltimore County

Imagine a world where your odds of surviving minor surgery were one to three. A world in which a visit to the dentist could spell disaster. This is the world into which your great-grandmother was born. And if humanity loses the fight against antibiotic resistance, this is a world your grandchildren may well end up revisiting.

Antibiotics changed the world in more ways than one. They made surgery routine and childbirth safer. Intensive farming was born. For decades, antibiotics have effectively killed or stopped the growth of disease-causing bacteria. Yet it was always clear that this would be a rough fight. Bacteria breed fast, and that means that they adapt rapidly. The emergence of antibiotic resistance was predicted by none other than Sir Alexander Fleming, the discoverer of penicillin, less than a year after the first batch of penicillin was mass produced.

Yet, contrary to popular belief, antibiotic resistance did not evolve recently, or in response to our use and misuse of antibiotics in humans and animals. Antibiotic resistance first evolved millions of years ago, and in the most mundane of places.

I am a bioinformatician, and my lab studies the evolution of bacterial genomes. With antibiotic resistance becoming a major threat, I’m trying to figure out how resistance to antibiotics emerges and spreads among bacterial populations.

A billion-years-old arms race

Most antibiotics are naturally produced by bacteria living in soil. They produce these deadly chemical compounds to fend off competing species. Yet, in the long game that is evolution, competing species are unlikely to sit idly by. Any mutant capable of tolerating a minimal quantity of the antibiotic will have a survival advantage and will be selected for – over generations this will produce organisms that are highly resistant.

So it’s a foregone conclusion that antibiotic resistance, for any antibiotic researchers might ever discover, is likely already out there. Yet people keep talking about the evolution of antibiotic resistance as a recent phenomenon. Why?

Resistance can and does evolve when bacteria are persistently exposed to a new antibiotic they have never encountered. Let’s call this the old-fashioned evolutionary road. Second, when bacteria are exposed to a novel antibiotic and are in contact with bacteria already resistant to this antibiotic, it is just a matter of time before they get cozy and trade genes. And, importantly, once genes have been packaged for trading, they become easier and easier to share. Bacteria then meet other bacteria, which meet more bacteria, until one of them eventually meets you.

Bacteria can evolve resistance to high levels of antibiotics in just days.

The rise and fall of sulfa drugs

For all their might, antibiotics are not the only substances capable of effectively killing bacteria (without killing us). A decade before the mass production of penicillin, sulfonamide drugs became the first commercial antibacterial agent. Sulfa drugs act by blocking an enzyme – called DHPS – that is essential for bacteria to grow and multiply.

Sulfa drugs are not antibiotics. No known organism produces them. They are chemotherapeutic agents synthesized by humans. No natural producer means no billion-year-old arms race and no pool of ancient resistance genes. We would expect bacteria to evolve resistance to sulfa drugs via the good old-fashioned way. And they did.

Just a few years after their commercial introduction, the first cases of resistance to sulfa drugs were reported. Mutations to the bacterial DHPS enzyme made sulfa drugs ineffective. Then penicillin and the antibiotic era came about. Sulfa drugs were relegated to a secondary role in medicine, but they gained popularity as cheap antimicrobials in animal husbandry. By the 1980s resistance to sulfa drugs was rampant and worldwide. What had happened?

At odds with resistance

To answer this question our research team took sequences of sulfa drug resistance genes from disease-causing bacteria and compared them to millions of “normal” versions of the DHPS enzyme in nonpathogenic bacteria.

The team identified two large groups of bacteria that had DHPS enzymes resistant to sulfa drugs. By studying their DNA sequences, we were able to show that these resistant DHPS enzymes had been present in these two groups of bacteria for at least 500 million years. Yet sulfa drugs were first synthesized in the 1910s. How could resistance be around 500 million years ago? And how did these resistance genes find their way into the disease-causing bacteria plaguing hospitals worldwide?

The clues left in gene sequences are too fuzzy to conclusively answer the latter, but we can certainly speculate. The bacteria we identified as harboring these ancient sulfa drug resistance genes are all soil and freshwater bacteria that thrive under the well-irrigated subsoil of farms. And farmers have been adding huge amounts of sulfa drugs to animal feed for the past 50 years.

The sublethal concentrations of sulfa drugs in the soil are the perfect setting for resistance genes to be transferred from these ancient resistant bacterial populations to other bacteria. All it takes is for one lucky bacterium to meet one of these ancient resistant ones in the subsoil. They trade some genes, one bacterium to the next, and resistance spreads until a newly minted resistant bacterium eventually makes it to the groundwater supply you drink from. You do the math.

Nothing new under the sun

As for why sulfa drug resistance genes would be around 500 million years ago, there are two plausible explanations. On the one hand, it could be that 500 million years ago there was a bacterium that synthesized sulfa drugs, which would explain the evolution of resistance. However, the lack of remnants from such a biosynthetic pathway makes this unlikely.

On the other hand, resistant bacteria may have been around just by chance. The argument here is that there are so many bacteria, and such diversity, that chances are that some of them are going to be resistant to anything scientists come up with. This is a sobering thought.

Then again, this is already the baseline for antibiotics. Like climate change, antibiotic resistance is one of those problems that always seem to be a couple decades away. And it may well be. A turning point for me in the climate change debate was a decade-old opinion piece in New Scientist. It stated that we should make every possible effort to prevent climate change, especially in the unlikely case that it was not caused by man, because that would mean that all we can do is palliate a natural phenomenon.

Our research points in the same direction. If resistance is already out there, drug development can offer only temporary relief. The challenge then is not to quell resistance, but to avoid its spread. It is a big challenge, but not an insurmountable one. Not feeding wonder drugs to pigs would do nicely, for starters.The Conversation

Ivan Erill, Associate Professor of Biological Sciences, University of Maryland, Baltimore County

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Flesh-eating bacteria cases on the rise and we need an urgent response


File 20180413 47416 1fmbesr.jpg?ixlib=rb 1.1
In Australia, cases of Buruli ulcer have been associated with coastal areas – like Victoria’s Bellarine Peninsula.
Bernard Spragg. NZ/Flickr, CC BY

Daniel O’Brien, University of Melbourne

Victoria is facing a worsening epidemic of flesh-eating bacteria that cause a disease known internationally as Buruli ulcer – and we don’t know how to prevent it. Also called Bairnsdale ulcer or Daintree ulcer, this disease causes destructive skin lesions that can lead to severe illness and occasionally even death.

Buruli ulcer is caused by the bacteria Mycobacterium ulcerans (M. ulcerans) and often results in long-term disability and cosmetic deformity.

An epidemic, or an outbreak, is when cases of a disease occur more often than expected in a given area over a particular period of time.

In 2016, there were 182 new cases in Victoria, which, at the time was the highest number ever reported. But the number of casesreported in 2017 (275) have further increased by 51%, compared with 2016 (182). The cases are also becoming more severe in nature and occurring in new geographical areas.

In Australia, Buruli ulcer is frequently reported from the Daintree region, and less commonly the Capricorn coast, of Queensland. Occasionally we’ve heard of cases from the NT, NSW and WA. But most reports come from Victoria, where the disease has been recognised since 1948.

Despite this, we still don’t know the exact environmental niche where the organism lives and how it is transmitted to humans.

Our article, published today in the Medical Journal of Australia, calls for an urgent investigation to answer some critical questions. These include finding out the natural source of M. ulcerans; how the infection is transmitted to humans; what role possums, mosquitoes and other species play in transmission; why the disease incidence is increasing and spreading into new areas in Victoria; and why cases are becoming more severe.

Why is Buruli ulcer such a problem?

Buruli ulcer occurs most commonly in the tropical regions of West or Central Africa, and is a significant public health problem there.

Ulcers are the most common form of this disease. But it can also manifest as a small swelling or lump below the skin, a plaque or as a cellulitic form, and can be complicated by bone or joint infection. The disease can affect all age-groups, including young children.




Read more:
Explainer: what is the flesh-eating bacterium that causes Buruli ulcer and how can I avoid it?


Treatment effectiveness has improved in recent years and cure rates have approached 100% with the use of combination antibiotics (rifampicin and clarithromycin). But these are expensive and not subsidised under Australia’s Pharmaceutical Benefits Scheme (PBS).

The treatments are also powerful and about one-quarter of people have severe side-effects including hepatitis, allergy or a destabilisation of other medical conditions such as heart disease or mental illness.

Buruli ulcer usually requires reconstructive surgery, like in the case of this 76-year-old man.
Author provided

Many people require reconstructive plastic surgery – sometimes with prolonged hospital admissions. On average it takes four to five months for the disease to heal, and sometimes a year or more.

All of this results in substantial costs through such things as wound dressings, medical visits, surgery, hospitalisation, and time off work or school.

What do we know about the bacteria?

M. ulcerans disease is concentrated in particular sites, and endemic and non-endemic areas are separated by only a few kilometres. In Africa it’s usually associated with wetlands, especially those with slow-flowing or stagnant waters. But in Australia it’s found mostly in coastal regions, like Victoria’s Mornington Peninsula.

We know the risk of infection is seasonal, with an increased risk in the warmer months. Lesions most commonly occur on areas of the body that have been exposed. This suggests bites, environmental contamination or trauma may play a role in infection, and that clothing is protective.

Human-to-human transmission does not seem to occur, although cases are commonly clustered in families, presumably as a result of similar environmental exposure.

The rest is unclear. Possible sources of infection in the environment include the soil, or dead plant material in water bodies such as lakes or ponds.

It may be transmitted to humans though contamination of skin lesions and minor abrasions – through trauma or via the bite of insects such as mosquitoes.

In Victoria, some possums in Point Lonsdale on the Bellarine Peninsula (an endemic area) were found to have Buruli ulcers and have high levels of M. ulcerans in their faeces. The location, proportion and concentration of M. ulcerans in possum faeces was also strongly correlated with human cases. But no M. ulcerans was found in possum faeces in nearby areas with no human cases.

So, it’s thought possum faeces might increase the risk of infection to humans in contact with that environment, or infection could be potentially transmitted by insects biting possums and then humans.




Read more:
Are mosquitoes to blame for the spread of ‘flesh-eating’ bacteria?


What should we do?

We need to understand the risk factors for M. ulcerans disease by comprehensively analysing human behaviour and environmental characteristics, combined with information on climate and geography.

It’s especially relevant that over the last two years, the number of cases have been increasing in the Mornington Peninsula, while decreasing in the adjacent Bellarine Peninsula. Studying this could allow us to pinpoint the risk factors that underlie the differing incidence patterns.

Once identified, more specific analysis can be performed to further assess the role of these risk factors. We can then explore targeted interventions such as modifying human behaviour, insect control, changes to water use and informed urban planning. Through this we have the best chance to develop effective public health interventions to prevent the disease, and promote more community education and awareness campaigns to help people protect themselves.

It will also facilitate the development of predictive models for non-affected areas that closely monitor these areas for the emergence of the organism. This knowledge can hopefully also be applied globally to benefit those affected overseas.

The ConversationWe need an urgent response based on robust scientific knowledge. Only then can we hope to halt the devastating impact of this disease. We advocate for local, regional and national governments to urgently commit to funding the research needed to help stop Buruli ulcer.

Daniel O’Brien, Associate Professor, University of Melbourne

This article was originally published on The Conversation. Read the original article.