I’ve touched on this topic a couple of times in the past, but it is deserving of its own entry. You’ve probably heard of antibiotic resistant bacteria and the minor crisis they are creating, so today let’s talk about how antibiotic resistance works, why it's a problem, and what is being done about it.
The Mechanism
An antibiotic is any substance that selectively kills bacteria and is thus useful as drugs for treating bacterial infections. There are numerous mechanisms by which an antibiotic kills bacteria such as inhibiting the production of a bacterium's cell wall, inhibiting the proteins bacteria use to copy DNA or make other proteins, or by cutting holes in a bacterium's cell membrane. Antibiotics can either be broad-spectrum (killing numerous bacterial species indiscriminately) or narrow-spectrum (targeted to kill a few species), both of which have their uses in medicine. These substances originated in nature, being secreted by fungi to prevent infection and eliminate competing bacteria. Humans now farm them to produce antibiotic drugs. Penicillin was the first such antibiotic drug, produced by Penicillium molds and first isolated in 1928. Today, over 100 antibiotic drugs are in use, each sorted into classes based on their chemical makeup and how they kill bacteria.
But just as with any obstacle, bacteria can learn to counter antibiotics. Bacteria have incredible genetic diversity meaning that for any antibiotic, there will be a few bacteria in any sample that won’t be strongly affected. The mechanisms by which bacteria can resist antibiotics are as varied as the mechanisms of antibiotics themselves, but a few include secreting enzymes that break down antibiotics, removing antibiotic molecules from themselves with protein pumps, or modifying the parts of the bacteria the antibiotic is supposed to attack so they’re no longer susceptible. Whatever method a bacterium uses to protect itself, evolution by natural selection means these resistant bacteria will be the most likely to survive and reproduce, so their daughter cells will carry the genes that made their parents resistant. Making matters worse, bacteria are also capable of exchanging genetic material between themselves, both directly via bacterial conjugation and by absorbing free-floating DNA left behind by dead bacteria, meaning the genes that grant resistance can spread quickly through a bacterial population or possibly between bacterial species. Having antibiotic resistant bacteria in one’s body isn’t necessarily an immediate problem; if a course of antibiotics kills 99% of a bacterial infection, that gives one’s immune system the space it needs to handle the 1% that is resistant. And antibiotic resistant bacteria aren’t any more dangerous in terms of the infections they cause, they’re just immune to a very specific type of poison. The real problems begin when an entire population of bacteria is resistant to multiple antibiotics and makes it out of one person’s body where it can infect other people.
The Crisis
For the past century, antibiotics have been a powerful superweapon against bacterial infections. In the 19th century, a quarter of all deaths in Western Europe were due to tuberculosis infections, which became so prevalent it affected the culture of the era in interesting ways. Bacterial pneumonia had a 25% mortality risk with that number being even higher amongst children. Even infected wounds were fatal in 80% of cases. Diseases such as syphilis, gonorrhea, and leprosy had no effective cure, leading to long-term disfigurement and disability. The deadliness of bacteria made surgeries far riskier, which stymied the development of surgical treatments. It can’t be understated how revolutionary the advent of antibiotics were, rendering some of humanity’s greatest monsters survivable and in some cases harmless. So much of our modern relationship to infection and death is built on this one class of drugs, and it’s beginning to slip through our fingers.
As early as the 1950s, researchers were observing patient bacteria samples that were resistant to common antibiotics like penicillin. This wasn’t considered a huge cause for alarm at the time, mostly because it was still the golden age of antibiotic development. New antibiotic drugs were still being discovered and put on the market at an astounding rate. If a particular antibiotic wasn’t working, you could just prescribe a different one. But after the 1960s, this rate of discovery began to slow down. All the obvious sources of new antibiotic substances had been researched and researchers were now focusing on modifying existing classes of antibiotics to create more potent strains with fewer side effects. No new class of antibiotics have been introduced since 1987,* giving doctors fewer options when combating resistant strains of bacteria. While the term ‘superbug’ isn’t a scientific term, it is colloquially used to refer to bacterial strains that are resistant to multiple antibiotics, sometimes all the antibiotic types that would normally be effective against said species of bacteria. Globally, 1.27 million people die per year due to infection from antibiotic resistant bacteria.
Timeline of the Discovery of New Antibiotic Classes
While antibiotic resistance is ultimately inevitable, there are ways we’ve misused antibiotics which have helped this process along. According to a recent poll, one in three people admitted that the last course of antibiotics they took were done so without a medical prescription, either by reusing pills from a previous prescription or obtaining them through other means. This is most common in rural or underdeveloped regions where medical access is harder and self-medication is necessarily common, but antibiotic misuse happens everywhere (the poll above was conducted in the European Union). Please do not do this. Antibiotics are only effective against bacterial infections and are often only effective against particular bacterial species. They are not effective against colds or any other viral infection, and it can be difficult to distinguish between bacterial or viral infections via symptoms alone. In most developed nations, only topical antibiotics can be obtained without a prescription because only a doctor can determine if antibiotics will be effective. It is also important to not cut short a course of antibiotics because one starts feeling better. It’s normal for symptoms to abate once one begins taking antibiotics because they kill off enough bacteria to suppress the infection. But this doesn’t mean that the infection has been completely purged from one’s body, just that they’re on the backfoot. It’s only with continued pressure that the infection can be completely eradicated. If this pressure isn’t maintained long enough, there could be survivors and they will be statistically likely to carry genes that grant resistance. The duration and dosage of antibiotic courses are determined by doctors based on what it will take to definitively end an infection with the fewest side effects. That said, at least part of this crisis can be attributed to clinical misuse, as overprescribing of antibiotics has also contributed to this crisis. This is usually done to placate a patient’s request or to err on the side of caution, and while this has become much less of a problem in recent decades as doctors actively work to combat antibiotic resistance, it is a thing that still happens.
The other major contributor to the development of antibiotic resistant bacteria is food and livestock production. Livestock animals are treated with antibiotics, often types and doses not used on humans due to concerns about side effects. Resistant bacteria can then spread to humans via contact with agricultural runoff, undercooked meat,** or direct interaction with infected animals. Making matters worse is the way antibiotics are used for farm animals. Factory farms cram animals together at high densities in order to maximize meat production. This would be the perfect breeding ground for infections which would tear through herds and reduce profits, so antibiotics are given to healthy animals as a preventative measure. Many dangerous superbugs were first identified in farm animals that then spread to humans. Later this year, new rules from the FDA will go into effect, making several veterinary antibiotics prescription-only, which will definitely be a step in the right direction. But unless similar laws are passed in other countries, this won’t be enough.
Solutions
Fortunately, scientists aren’t passive and solutions to this crisis are being researched. In the short-term, health agencies such as the WHO and CDC are identifying antibiotics that are most at risk of becoming ineffective and reducing their usage to that of last resort. Antibiotics that are still effective against the most resistant superbugs are also being reserved for those resistant infections to keep them effective in the long-term. New prescribing measures are being used to ensure antibiotics aren’t overprescribed and new labeling rules are being implemented to educate the public on proper antibiotic usage. For the long term, new methods of treating bacterial infection are being researched and explored, such as;
New Antibiotics
The reasons for the discovery void in antibiotics research are economic as well as scientific. The first classes of antibiotics were discovered via the Waksman Platform, an experimental method where a culture of antibiotic-producing soil bacteria is grown next to a culture of common infectious bacteria, separated by a barrier. If the infectious bacteria stop growing, chemical samples are taken to identify the substance and that culture of antibiotic producers are grown further. This worked well for a while, but we’ve since identified all of the common soil antibiotics. Other methods of identifying antibiotic substances require more time and money to research. Add to this that any new antibiotic would be competing against a hundred other drugs and doctors are now deliberately trying to use antibiotics as little as possible, and pharmaceutical companies aren’t investing in antibiotic development due to the lack of profitability.
But this situation isn’t hopeless. As biology becomes more data-driven, digital libraries have been curated containing the structures of millions of biological molecules from every organism imaginable. We don’t always know what role these molecules play in their associated organism, but these databases allow scientists to do research using powerful computers. These libraries are just starting to revolutionize the field of drug discovery, the identification of molecules which could have pharmaceutical uses. Algorithms are being tested that could identify potential new antibiotics by comparing parts of molecules to known antibiotics or by simulating their interactions with molecules from bacteria. As computers become more powerful, the discovery of new antibiotics could once again be as easy as it was in the golden age.
Bacterial Vaccines
While we normally think of vaccines as a treatment for viruses, vaccines can be developed for bacterial infection as well. There currently exist vaccines for the bacteria that cause typhus, diphtheria, tetanus, whooping cough, cholera, bubonic plague, and certain forms of pneumonia, tuberculosis, and meningitis. The reason bacterial vaccines aren’t more common is that bacteria are far more complex organisms than viruses, making it harder to identify the most effective antigens which will give consistent, long-lasting immunity. But with advances in mRNA vaccines (both before and after Covid vaccine development), researchers are optimistic that vaccines against common bacterial infections will become more effective. Vaccines are much harder to develop resistance to than antibiotics and their development is comparatively easy. It's important to remember that vaccines are purely preventative medicine; they won’t help someone who is already sick. But we’ve already talked about how antibiotics are being inadvisably used as prophylactic measures among livestock, so a proper prophylactic against bacterial infection would have a market. And since we already vaccinate children against several bacterial infections, adding more to that list would be a step in the right direction.
Autoinducer Inhibitors
Believe it or not, bacteria have a social structure. Bacterial infections often depend on coordination between individual bacteria in order to reproduce, move as a collective, and produce substances that defend the collective. Bacteria coordinate these actions by secreting autoinducers, proteins that other bacteria can detect. The surrounding concentration of autoinducers can tell a bacterium how large its colony is and where it’s located in the colony. This regulates the behavior of the bacteria within the colony and the colony as a whole, similar to eusocial insects like bees and ants. Studies have been done where bacteria cultures were treated with substances that bind to autoinducer proteins to make them useless. It was found that without autoinducers, the colony breaks down, making individual bacteria less virulent, more vulnerable to the immune system and other antibiotics, and potentially lead to bacteria competing with each other.
What makes autoinducer inhibitors so promising as a potential antibiotic is that it might be impossible for any bacteria to develop a resistance to them. Antibiotic resistance works via natural selection; to be resistant to an antibiotic significantly increases a bacterium’s chances of survival and reproduction. But while it is possible for a mutation to make a bacterium resistant to autoinducer inhibitors, being resistant to them won’t significantly improve a bacterium’s odds of survival. Being the one bacterium that can still talk won’t help you if no one else can hear. The colony collapses into billions of competing individuals who are far easier to kill off by the immune system or with other drugs. Since the resistant bacteria had the same death rate as the vulnerable ones, large scale resistance to autoinducer inhibitors can’t develop. Research is still ongoing on how this process works and if autoinducer inhibitors would be effective as a drug, but it’s a promising concept.
Phage Therapy
I’ve talked before about bacteriophages, viruses that exclusively infect bacteria. Because bacteria are so simple compared to our own cells, the viruses that prey on them have an easier job. Every day, 40% of all the world’s ocean bacteria are killed by phages before restoring their numbers through rapid reproduction. And since our cells are so different from bacteria, there’s no chance a phage could ever evolve to infect a human cell. With all that in mind, considerable research has gone into using bacteriophages to treat bacterial infections. Since phages are “living” things, they could adapt to overcome bacteria’s resistance to them as fast as that resistance could evolve. There have already been experimental cases where patients dying of highly antibiotic resistant bacterial infections were given an intravenous cocktail of bacteriophages and fully recovered. There are still challenges to overcome; phages aren’t as shelf stable as antibiotics, there’s a lot of unknowns regarding dosage, delivery, and side effects, and bacteria do have a low-but-not-zero chance of developing resistance to phages (though there is evidence that the adaptations that make a bacteria resistant to phages ironically makes them more vulnerable to traditional antibiotics). But phage therapy might be the most promising potential alternative to traditional antibiotics currently in development.
When doctors and scientists say we are coming to the end of the era of antibiotics, this does not mean we are destined to return to an era when a paper cut could kill you. But since they were discovered, antibiotics were modern medicine’s magic bullet; a single tool that could fix any bacterial infection with no need for second thoughts. In hindsight, we probably should never have been doing that. The coming era will likely be one of more consideration; where we have a complex toolset whose usage we tailor to the needs of individual patients, which is a direction we’re heading in for all medicine. This is a crisis, but it’s a crisis we’re working to fix and in all likelihood will fix.
Remember whenever you are prescribed antibiotics, take all of them as directed, don’t stop because you’re feeling better, and don’t save or share them.
For More Details
*It’s important to note that new antibiotics have been developed, but each one was in an existing class. Every antibiotic in a class will have the same mechanism of attack, have similar chemical structures, and are often discovered from the same source. For example, the penicillin class contains multiple antibiotics that kill by preventing the formation of a bacterium’s cell wall, such as the original penicillin, amoxicillin, oxacillin, and methicillin. Different drugs within the same class can be more effective against certain bacterial species or have different side effects. If a bacterial strain is resistant to a particular antibiotic, it will likely be resistant to all other drugs within that antibiotic’s class.
** To be clear, the risk from eating meat from animals treated with antibiotics does not come from the antibiotics themselves. These traces of antibiotics are at such low levels that they won’t affect the bacteria in the consumer’s body. The risk comes from the potential spread of antibiotic-resistant bacteria that was bred in the animal’s body, which can be prevented the same way any foodborne illness is prevented (e.g. with hygienic handling of the meat and cooking meat thoroughly).
Comments