The drugs that have protected us from the ubiquitous bacteria for more than seventy years are slowly losing their grip, and we need a new weapon to fight infections. Disease-causing bacteria are becoming immune to the antibiotics that once killed them, even to drugs that were once considered the last line of defense.
Antibiotic-resistant (antibiotic-resistant) bacteria kill about one percent of the people they infect, even in developed countries. And if this is ignored, they will kill five times more people every year.
“Many things that we take for granted at the moment, like a cesarean section, or hip replacement, or organ transplants, without antibiotics, will become very difficult,” says François Franceschi, program manager for therapeutic development in the bacteriology and mycology department of the National Institute of Allergy and infectious diseases.
People with weakened immune systems are especially vulnerable, but in the post-antibiotic world everyone without exception will be at risk.
“People say that in the post-antibiotic era, antibiotics will no longer be able to help us with even the smallest scratch,” says Cesar de la Fuente, a bioengineer at the Massachusetts Institute of Technology.
To fight resistant bacteria, we turn to new allies, such as viruses, that only attack bacteria; nanoparticles and tiny proteins produced by the immune systems of various organisms. Each tool has its own advantages and disadvantages, which is why scientists are studying a variety of approaches.
“A lot of people in the field are currently looking for alternative strategies to add to our arsenal,” says Timothy Lu, also at MIT. "It's not that each of them is trying to invent their own silver bullet that will save us from bacteria for the rest of our lives, but rather studying the problem from different angles."
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Here are some ways we can help us deal with unwanted bacteria.
Disarm the invaders
Bacteria do not always need to be killed to neutralize. Some treatments target germs indirectly by depriving them of their weapons. The bacteria will be in place, but the consequences of infection will not be serious, and the immune system will have a chance to fight the infection on its own.
If your drug doesn't actually kill bacteria, they will have less incentive to build resistance to it. It will take longer for resistance to develop because the bacteria won't actively fight the drug, Franceschi says.
Many bacteria release toxins that damage host cells. One of the most common types of toxins is called pore-forming, which punctures holes in cells. It is isolated by methicillin-resistant Staphylococcus aureus, Escherichia coli, Listeria bacteria, anthrax bacteria and venom from snakes, scorpions and sea anemones.
Liangfang Zhang figured out how to eliminate these toxins. “You take away the weapons and they get much weaker,” says Zhang, a nanoengineer at the University of California, San Diego. It coats the nanoparticles with a sweet target - membranes made up of red blood cells. The red blood cell acts as a decoy, sucking in toxin that would otherwise attack healthy cells. “It’s like a sponge sucking out toxins,” Zhang explains.
In his first study, he showed that nano-sponges absorbed toxins without harming mice. Zhang's work with nanoparticles as decoys this year was one of 24 projects to receive funding from the National Institutes of Health. He hopes to start clinical trials in humans as early as next year.
Nanoparticles, which are often made from plastics or metals such as silver, can also weaken bacteria by destroying their protective cell membranes or causing DNA damage. Nanoparticles are easy to work with because they build themselves. “You control the temperature, the solvent, and everything else, and these molecules assemble themselves into a nanoparticle,” Zhang says.
Nanoparticles can be more expensive than traditional antibiotics. And getting them to the right place in the body can be a challenge too. Another challenge is making sure the nanoparticles are made of materials that will not elicit an immediate immune response, and will break down over time so they don't build up in the body.
Questions remain regarding the long-term safety of some of these things, Lou says.
Special delivery
Alternative treatments can be applied to make existing antibiotics more effective. For example, scientists are now studying how nanoparticles could be used to deliver anti-cancer drugs and antibiotics.
Antibiotics are distributed throughout the body and are toxic in high doses. With the help of nanoparticles, concentrated doses of drugs could be released. Thousands of drug molecules could be shoved inside a single nanoparticle.
“They can easily just attach to the membrane and gradually release the drugs directly onto the bacteria,” Zhang says. Consequently, a more effective load could be more accurately targeted without increasing the total dose of the drug. In this way, the mechanism of bacterial resistance could be suppressed - they simply would not develop resistance against point-acting antibiotics.
The problem with nanoparticles, like many other tools, is that the immune system sees them as a threat. “They are very similar in size to viruses. Our body will learn to defend itself against these nanoparticles, or viruses, if you don't protect them."
Zhang and his colleagues have camouflaged nanoparticles in jackets made from platelet membranes, the cells that help blood clot. From the side, the nanoparticles are similar to these miniature blood cells. Some bacteria are attracted by platelets - with their help, they are masked from the immune system. Platelet-coated nanoparticles could play twice, recruiting invaders to detonate them with a drug.
All nanoparticles will release drugs in the presence of bacteria, Zhang says. With the help of platelet-coated particles, he has already cured mice infected with the multi-antibiotic-resistant strain of MRSA.
Direct attack
Sometimes, however, half measures do not help. There are alternatives to traditional antibiotics that can kill bacteria. One strategy is to create artificial versions of antimicrobial peptides (AMPs), which are part of the innate immune response in microbes, plants and animals (like the Tasmanian devils). These components attack the pathogen's membrane and wreak havoc within the cell.
As part of a recent project, de la Fuente worked with Lou and others to select a non-toxic AMP found in simple marine animals called tunicates. The scientists added several amino acids to the basic setting, improving its ability to treat mice infected with antibiotic-resistant strains of E. coli, or MRSA. Fortified AMP also strengthens the rodent's immune system, reduces inflammation, and calls for help in the form of white blood cells.
Antimicrobial peptides can defeat a wide range of pathogens, and bacteria have a hard time developing resistance to them. “Compared to conventional antibiotics, these peptides are more effective in many cases,” says de la Fuente.
AMPs are made up of relatively short chains of amino acids, the building blocks of protein. Therefore, they are quite simple (although expensive) to build. “We have yet to bring the cost down,” says de la Fuente. Scientists are exploring ways to make AMPs cheaper by programming microbes so they don't rely on a machine and let the microbes do it themselves.
Nevertheless, there are concerns that AMP may attack the host's cells. And as with many antibiotic alternatives, sending peptides to the right place in a high enough concentration to remain effective can be a challenge. In the short term, local application is more likely, de la Fuente said. These peptides could be incorporated, for example, into a cream that could be applied to an open wound or to the site of an infection on the skin. They could also be used to cover tables, computers, surgical instruments or catheters to keep germs from colonizing them.
Re-sensitization
Another way to weaken bacteria is to rid them of the resistance they have developed to antibiotics. For such missions, viruses that specialize in eating bacteria, bacteriophages, could be used.
Bacteriophages are extremely effective killers of bacteria, but through genetic engineering, scientists could give them new abilities, including restoring the sensitivity of bacteria to traditional drugs.
Reprogrammed bacteriophages can become obsessed with bacteria carrying genes that confer antibiotic resistance, remove this ability, or kill bacteria. When the resistant microbes are destroyed or rendered harmless, the remaining population will be vulnerable to antibiotics.
Another method that allows bacteria to resist antibiotics is by secreting compounds that create a biofilm through which the drug cannot penetrate. It is possible to create bacteriophages that will eat up biofilm.
In nature, bacteriophages can directly kill bacteria. Some of them plug their DNA into bacteria, and to free themselves, they simply eat through the cell wall, blowing up the cell, Lu says. Others act as parasites.
Bacteriophages were discovered about a hundred years ago. Antibiotics have replaced them in the United States, but they continue to be used in Russia and in some Eastern European countries. As antibiotic-resistant bacteria grow, scientists are again turning to bacteriophages - they are just as effective in treating people, just clinical trials have not yet confirmed this.
One of the advantages of these viruses is that they can replicate themselves. You can put only a small amount and kill many bacteria. And since they need living cells to reproduce, they will stop reproducing as soon as all the host's cells are destroyed.
However, like other alternatives, bacteriophages can trigger an immune system response. “If you inject any virus or foreign peptide into the human body, there is always a chance that a reaction will follow,” says Lu. Another concern is that some phages may pick up genes associated with antibiotic resistance and pass them on to other bacteria.
But they are unlikely to damage human tissue. Bacteriophages do not multiply in human cells. We have a bunch of bacteriophages inside us - it's hard to say that they are strangers to us.
Personal contact
Several alternative treatments could be tailored to target specific germs. Here again, bacteriophages are ideal candidates. “They are essentially the natural enemy of bacteria,” Lu says. Usually, "if you find bacteria, you also find bacteriophages."
Traditional antibiotics often kill bacteria indiscriminately - including in our body's natural microbiome, which plays an important role in our health. It is carpet bombing that kills everything.
Viruses offer a more personalized approach. “You can try to keep the good bacteria while killing the bad bacteria,” Lu says.
However, this specificity is also a double-edged sword. In order to cover a sufficient number of different bacteria that can infect a patient, many viruses will have to be mixed in the cocktail. Although bacteriophages are not very expensive to grow, cocktails of a variety of viruses are another matter entirely.
Lou is working on cocktails of bacteriophages built on safe forests. By determining the area that the bacteriophages should infect, you can attack different bacteria, direct the bacteriophages in different directions. It remains only to figure out how to do it.
Be that as it may, it is difficult to create an effective drug without knowing what is causing the infection. If you go to your doctor, he will not be able to provide you with narrow-spectrum treatment if he does not know what bacteria are bothering you.
Doctors need faster diagnostic methods so they can figure out the type of target bacteria and how resistant they are to traditional antibiotics. Lu and his colleagues are working to create fast, cheap diagnostics. When they infect their target bacteria, they light it up with the same protein that fireflies use. Just give the bacteriophage sample to the patient and “you can tell if the sample is glowing or not, bacteria is present in it or not,” Lu says.
Wide arsenal
These are not all the weapons we add to our arsenal. Scientists are exploring other options, like sending other bacteria to fight pathogens, finding new antibiotics, and using antibodies, and more.
“You can hardly rely on one method or one technology to root out the whole problem,” Zhang says. Studying superbugs from different angles, combining new tactics and traditional methods of treatment, will expand our arsenal.
It will take several years before new instruments are approved for widespread use. And for a while, alternative antimicrobial methods will only be used when antibiotics no longer work. The cheapness and effectiveness of antibiotics is the main reason why they are difficult to refuse. But in the long run, this will be the only option.
ILYA KHEL