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.
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.
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.
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.
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.
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.
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
How are vaccines made to kill a virus? Layla, aged 7
Thanks Layla. This is a very important question, especially now, as scientists all around the world are working hard to develop a vaccine to protect us against the coronavirus. Actually, scientists are trying to find vaccines for many different diseases.
To understand how vaccines are made, we first need to understand how viruses make us sick, and how special cells in our bodies defend us against infections.
Curious Kids: what are cells made out of?
Viruses make us sick when they invade our cells. The way this works is kind of complicated — us scientists have to study for many years to fully understand it. But you can think of it like this.
Viruses can get inside our cells by using a special key that fits into a lock on the outside of our cells. Once inside, the virus hijacks the cell, forcing it to make more virus by turning cells into tiny virus factories.
This is stressful for our cells, which can make us start to feel sick. The virus made in the virus factories can spread the infection through our body, to make us even sicker.
It can also spread from our body to infect other people, and make them sick too.
Your immune system is made up of immune cells — very special cells that live all throughout your body. Their job is to look out for any signs of an infection and defend all the other cells in your body when there is a threat.
There are many types of immune cells that work as a team to stop and even kill the virus. Two very important immune cells are B cells and T cells.
B cells make a secret weapon called antibodies. Antibodies are tiny Y-shaped particles that are incredibly sticky — they stick all over the key on the virus so it no longer fits into the lock on our cells. This stops the virus from getting in and causing an infection.
If a virus does sneak past the B cells and get into our cells, T cells can deal with it — they are the ninjas of our immune system! They kill any cells that get infected to stop the virus from spreading within our body.
Our body comes across viruses — like the common cold, for example — every day, and they don’t always make us sick because our immune cells can protect us. But our immune cells are much better at their job if the virus is one they’ve seen before.
If we come across a new virus — like the coronavirus, for example — our immune cells can’t recognise it straight away. This gives the virus a chance to infect our cells and it can start to make us sick.
All vaccines contain a little piece of the virus, which our immune cells pick up and start to show to each other. Our B cells and T cells can then recognise that little piece of virus and remember it, sometimes for years.
The next time we see that virus, our immune cells recognise it straight away and kick into action.
If our immune cells can act quickly enough, we won’t get sick, and our bodies won’t make more virus that could make other people sick.
So, we hope that answers your question Layla. Your immune system is a powerful defence force — it protects you every day from infections. But sometimes it needs a little help from a vaccine, especially with a new virus it hasn’t seen before.
Hello, curious kids! Have you got a question you’d like an expert to answer? Ask an adult to send your question to firstname.lastname@example.org
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.
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.
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.
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.
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.
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.
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.
This article is supported by the Judith Neilson Institute for Journalism and Ideas.
Viruses are little more than parasitic fragments of RNA or DNA. Despite this, they are astonishingly abundant in number and genetic diversity. We don’t know how many virus species there are, but there could be trillions.
Past viral epidemics have influenced the evolution of all life. In fact, about 8% of the human genome consists of retrovirus fragments. These genetic “fossils” are leftover from viral epidemics our ancestors survived.
COVID-19 reminds us of the devastating impact viruses can have, not only on humans, but also animals and crops. Now for the first time, the disease has been confirmed in a tiger at New York’s Bronx Zoo, believed to have been infected by an employee. Six other tigers and lions were also reported as “showing symptoms”.
According to the BBC, conservation experts think COVID-19 could also threaten animals such as wild gorillas, chimps and orangutans.
While virologists are intensely interested in how viruses mutate and transmit between species – and understand this process to an extent – many gaps in knowledge remain.
Most viruses are specialists. They establish long associations with preferred host species. In these relationships, the virus may not induce disease symptoms. In fact, the virus and host may benefit each other in symbiosis.
Occasionally, viruses will “emerge” or “spillover” from their original host to a new host. When this happens, the risk of disease increases. Most infectious diseases that affect humans and our food supply are the result of spillovers from wild organisms.
The new coronavirus (SARS-CoV-2) that emerged from Wuhan in November isn’t actually “new”. The virus evolved over a long period, probably millions of years, in other species where it still exists. We know the virus has close relatives in Chinese rufous horseshoe bats, intermediate horseshoe bats, and pangolins – which are considered a delicacy in China.
Past coronaviruses, including the severe acute respiratory syndrome coronavirus (SARS-CoV), have jumped from bats to humans via an intermediary mammal. Some experts propose Malayan pangolins provided SARS-CoV-2 this link.
Although the original host of the SARS-CoV-2 virus hasn’t been identified, we needn’t be surprised if the creature appears perfectly healthy. Many other coronaviruses exist naturally in wild mammal and bird populations around the world.
Human activity drives the emergence of new pathogenic (disease-causing) viruses. As we push back the boundaries of the last wild places on Earth – felling the bush for farms and plantations – viruses from wildlife interact with crops, farm animals and people.
Species that evolved separately are now mixing. Global markets allow the free trade of live animals (including their eggs, semen and meat), vegetables, flowers, bulbs and seeds – and viruses come along for the ride.
Humans are also warming the climate. This allows certain species to expand their geographical range into zones that were previously too cold to inhabit. As a result, many viruses are meeting new hosts for the first time.
Virus spillover is a complex process and not fully understood. In nature, most viruses are confined to particular hosts because of specific protein “lock and key” interactions. These are needed for successful replication, movement within the host, and transmission between hosts.
For a virus to infect a new host, some or all protein “keys” may need to be modified. These modifications, called “mutations”, can occur within the old host, the new one, or both.
For instance, a virus can jump from host A to host B, but it won’t replicate well or transmit between individuals unless multiple protein keys mutate either simultaneously, or consecutively. The low probability of this happening makes spillovers uncommon.
To better understand how spillovers occur, imagine a virus is a short story printed on a piece of paper. The story describes:
The short story also has instructions on how to make a virus photocopying machine. This machine, an enzyme called a polymerase, is supposed to churn out endless identical copies of the story. However, the polymerase occasionally makes mistakes.
It may miss a word, or add a new word or phrase to the story, subtly changing it. These changed virus stories are called “mutants”. Very occasionally, a mutant story will describe how the virus can live inside a totally new host species. If the mutant and this new host meet, a spillover can happen.
We can’t predict virus spillovers to humans, so developing vaccines preemptively isn’t an option. There has been ongoing discussions of a “universal flu vaccine” which would provide immunity against all influenza virus mutants. But so far this hasn’t been possible.
Despite how many viruses exist, relatively few threaten us, and the plants and animals we rely on.
Nonetheless, some creatures are especially dangerous on this front. For instance, coronaviruses, Ebola and Marburg viruses, Hendra and Nipah viruses, rabies-like lyssaviruses, and mumps/measles-like paramyxoviruses all originate from bats.
Given the enormous number of viruses that exist, and our willingness to provide them global transport, future spillovers are inevitable. We can reduce the chances of this by practising better virus surveillance in hospitals and on farms.
We should also recognise wildlife, not only for its intrinsic value, but as a potential source of disease-causing viruses. So let’s maintain a “social distance” and leave wildlife in the wild.
Here is a funny take on computer viruses and the battle to beat them: