The Rise of Superbugs: A Looming Health Crisis

Less than a hundred years ago, a few doses of penicillin were enough to instantly bring a dying person back to life – or at least that’s how it may have seemed to observers. Now, increasingly, we encounter situations where bacteria simply shrug off antibiotics. Every year, such bacteria spread further and further, and more and more antibiotics become less useful. The reason for this is antibiotic resistance – a gradual decrease in the sensitivity of pathogens to drugs.

Resistance is incredibly dangerous – at some point, a superbug may appear that is resistant to everything, including “last resort” antibiotics that are carefully guarded and used, well, as a last resort (and the genes for resistance to them have already appeared!). Today, we’ll talk about how resistance develops, how we got there and, most importantly, what it threatens us with. And we’ll also ask ourselves an existential question: what can we do about it?

Chance and luck, or hard work?

Almost everyone has heard the story of the British biochemist Alexander Fleming and his forgotten Petri dish, in which, during his vacation, the mold grew, killing the colonies of bacteria around it. This is how, in 1928, the antibiotic penicillin was discovered. Well, no, not quite that easily: despite the fact that this tale is usually presented as a funny story about the forgetfulness and sloppiness of the great scientist, it is about something completely different. It was not enough to grow mold in the dishes: it was necessary to notice it, assess the consequences, understand why this happens, isolate the active substance, conduct hundreds of confirmatory experiments and, most importantly, convince the scientific community that the resulting drug is a salvation for many hundreds of thousands, if not millions, of lives.

It is worth mentioning that there were suspicions about the existence of antibiotics before Fleming: American, Russian and European scientists worked with fungus long before the 1920s. And in general, the folk tradition of different cultures often suggested using moldy bread. But only Fleming managed to prove clearly that antibiotics were humanity's future. He also managed – and here, perhaps, we can attribute this to luck – to “infect” other scientists with his interest. As a result, by the beginning of World War II, penicillin began its triumphant march, and Fleming, together with two other scientists – the German-born British Ernst Chain and the Australian Howard Florey – received the Nobel Prize in 1945. At the same time, Fleming warned the scientific community and predicted that small doses of antibiotics would result in ‘‘microbes [that] are educated to resist penicillin.’’ He turned out to be right: by the beginning of the 1950s, such bacteria had already appeared, which is why it was necessary to make new antibiotics urgently – synthetic ones – with a slightly modified structure.

In 1942, the second antibiotic, streptomycin, was discovered accompanied by quite a scandal. Streptomycin was discovered by a young graduate student, Albert Schatz, who worked under the guidance of the venerable scientist Selman Waksman. He, in turn, did a lot to make streptomycin a truly effective and marketable drug. But only Waksman received the Nobel Prize “for the discovery of streptomycin, the first antibiotic effective in the treatment of tuberculosis.”

After penicillin and streptomycin, the scientific community focused on finding new antibiotics.

The houses of the three little pigs

Time passed, and bacteria, like all living things, did not stand still. With the challenges posed by antibiotics, they evolved, developed and acquired resistance.

The resistance of bacteria to certain antibiotics can be analogized to the houses of the three little pigs from the famous fairy tale. An antibiotic (the wolf) will destroy some houses (bacteria) with one poke, but there are some that it cannot destroy: they have resistance to such a “wolf”.

The mechanisms of resistance depend on the mechanisms of action of antibiotics. A drug can have a bactericidal effect – destroy a pathogen, or it can be bacteriostatic – slow down its growth and the development of a colony. In general, there are several main mechanisms by which antibiotics destroy bacterial houses.

Firstly, antibiotics can destroy the cell wall, for example, by affecting the activity of enzymes important for its formation. The cell wall is a strong polymer shell that covers the cell and gives it resistance. Destroying the wall means leaving the bacterium defenseless. β-lactam antibiotics, which include penicillin, cephalosporins and carbapenems, are a large group that affect the cell wall and all have similar mechanisms of action. Due to their similarities, if a patient is allergic to, for example, penicillin, they should not be given other antibiotics from this class as they may react equally to structurally similar drugs. This phenomenon is known as “cross-reactivity”. Bacteria that are resistant to this class of drugs have genes that allow them to disrupt the action of the antibiotic directly (many staphylococci, for example, can simply “cut” lactam antibiotics), have changed the structure of their enzymes or do not have a cell wall at all (like small mycoplasmas). To avoid such issues, some modern drugs are produced with an additive – for example, an inhibitor of the lactam ring cutting enzyme (so-called combination drugs).

Secondly, antibiotics can bind to the ribosome. A blocked ribosome prevents the bacterium from synthesizing proteins. Streptomycin, for example, has a bacteriostatic effect by binding to the 30S subunit of the bacterial ribosome. This leads to the breakdown of polyribosomes and defects in protein synthesis.

Thirdly, antibiotics can prevent DNA synthesis, which is how quinolone antibiotics act. This may happen by a number of means, from directly binding DNA chains to inhibiting important enzymes.

There are also some other ways to kill bacteria, such as disrupting the stability of their membranes or blocking respiratory enzymes. But those that have mutations leading to a changed structure, products that destroy antibiotics or changes to the permeability of membranes for the drug so that as few of its molecules as possible end up inside the cell survive. Bacteria evolve, regardless of what exactly we offer them.

Unfortunately, these “superpowers” are not limited to the individual bacterium and its progeny either. Genes encoding these resistance abilities can be shared with others via plasmids, extrachromosomal DNA that usually carry very few genes and are easily passed on to a “neighbor.”

And we help them exchange resistance genes through some of our actions such as discarding garbage. Polyethylene is an excellent substrate, and, according to a 2023 article, bacteria form dense biofilms on plastic in rivers where resistance genes can then spread more easily through these bacterial communities.

Given the speed at which bacteria reproduce, the emergence of a superbug is not a question of if but when.

Spread of resistance

Every year, the World Health Organization (WHO) and other agencies publish open reports on the state of antibiotic resistance. Every year, the numbers in these reports are frightening. Global research, based on data from 2000 to 2023 from 195 countries, shows a 65% increase in resistant infections. It was also mentioned that around 4.95 million deaths annually are attributed to antibiotic resistance. Another study from 2016 warned that by 2050, the annual death toll will increase to 10 million people. If everything continues as it is now, very soon the scourge of humanity will appear – a superbug resistant to everything that we can try to counteract it with. In 2015, WHO offered to create the Global Antimicrobial Resistance Surveillance System (GLAAS), which registers data on resistance from more than 100 countries around the world.

In the same year, resistance to colistin, one of the “last resort” antibiotics, was first recorded. Although colistin is not typically used to treat human diseases due to its strong toxicity, it is used in veterinary medicine. Therefore, a number of bacteria have unfortunately already developed resistance.

Already we see isolated cases of highly resistant bacteria, the frequency of which is increasing, with spread between locations. For example, in 2022, scientists from Brazil described a case of infection caused by Klebsiella pneumoniae, resistant to all used drugs. The patient died, and when the researchers received genome data of the infecting bacteria, they discovered this strain had previously been found in the United States.

Bacteria resistant to a variety of antibiotics are found everywhere: from the International Space Station to tribes that are not very connected to the “big” world. Antibiotics are used directly in farm animals and pets, but even the microbiota of wild animals, chimpanzees for instance, are already showing resistance! Other primates, baboons, for example, are not far behind. Evidence suggests that the closer a species lives to humans, the greater the likelihood that their microbiota will contain antibiotic resistance genes . And it can easily come back to us, providing recirculation of resistance genes between different populations.

Escherichia coli (E. coli) is adapting rapidly, especially in overcrowded areas where the population has limited access to health services. For example, in West Bengal, India resistance to macrolides in E. coli increased from around 5% to 30% from 2008 to 2013, and to tetracyclines from around 10% to 60%! In Europe, the situation has improved in recent years in some respects: for example, a report based on 2019–2023 data on bacterial diseases of the bloodstream showed that E. coli resistance increased by 21.9% to third-generation cephalosporins, while resistance to other antibiotics decreased. The situation with fluoroquinolones remains a little more dangerous (Figure 1).

Figure 1: Percentage of invasive isolates of E. coli resistant to fluoroquinolones (ciprofloxacin/levofloxacin/ofloxacin) by country for the WHO European Region, 2021. Credit: Antimicrobial resistance surveillance in Europe,2023, reproduced under a Creative Commons Attribution 4.0 International License.

But E. coli isn’t the only problem species. The resistance of Pseudomonas aeruginosa (P. aeruginosa), which causes abscesses and other purulent processes, is concerning and its resistance is astounding (Figure 2).

Figure 2: Total number of invasive P. aeruginosa isolates tested (n = 13,689) and AMR percentage (%) per phenotype in the EU/EEA in 2021. FQs, fluoroquinolones; PIP/TAZ, piperacillin-tazobactam; CAZ, ceftazidime. Credit: Antimicrobial resistance surveillance in Europe, 2023, reproduced under a Creative Commons Attribution 4.0 International License.

Staphylococcus aureus (S. aureus) is responsible for most of the so-called “hospital-acquired” infections and can cause various issues, from pneumonia and meningitis to abscesses and sepsis. S. aureus is a harmless commensal on the mucous membranes of about 20% of people worldwide, and remains silent until the immune system fails. Since the end of the last century, methicillin-resistant S. aureus (MRSA), which is resistant to all β-lactam antibiotics, has spread. Cases of hospitalization due to infection caused by it are becoming more frequent. These bacteria have acquired a plasmid containing the mecA gene, which prevents antibiotics from inactivating enzymes necessary for the synthesis of the cell wall. In a 2019 report, S. aureus was named 1 of the 6 main pathogens causing resistance-related deaths: during this year alone, it claimed up to 100,000 lives.

According to a report published in the Lancet in 2024, approximately 1.14 million people died from infections caused directly by antibiotic resistant bacteria in 2021 (with the majority of them being S. aureus). Compared with 1990, mortality from antibiotic resistant bacteria has decreased by more than 50% among children, but has increased by more than 80% among adults aged 70 and older.

What is especially interesting (and alarming) is that resistance is now being noticed in fungi too. In a 2017 article, researchers described a candida fungus, Candida auris, that has multiple resistance to antifungal drugs.

The only question - why?

What factors are promoting the development of resistance?

There are quite a few. First of all, there is, of course, self-medication, poor stewardship and decreased compliance. Antibiotics act selectively, and the choice of drug must be rational. Monobactams, for example, simply will not work on an infection caused by Gram positive bacteria. If your infection is caused by them and you take a monobactam, the problematic infection will not go away, But it will apply selective pressure to the Gram negative bacteria of your microbiota, promoting survival and success of those with resistance to monobactams that may cause problems in the future Sometimes an antibiotic is not needed at all: in some societies, there is a myth that antibiotics should be taken for a viral disease, which in reality they cannot treat. In some cases of viral infection, a doctor may prescribe an antibiotic to prevent a secondary bacterial infection from developing on top of the viral infection, but this is an exceptional case and typically only used in the vulnerable.

As for compliance, it's a bit different. The antibiotic may be correct, but the patient will often still be required to self-administer at home. Each course of antibiotics should be taken in full, but people forget or decide they know better because they think they’ve already recovered and don't need to take any more. In these situations, some bacteria can survive, either because the concentration of the antibiotic is not great enough to kill them or because they have mutations that lessen the impact the antibiotic has on them. Failure to complete antibiotic treatments allows these more resilient bacteria to survive, proliferate and spread.

In addition, we travel much more now. Traveling is also a "good" way for bacteria to acquire resistance: according to literary data, up to two thirds of United States international tourists bring with them not only souvenirs, but also resistant E. coli. The more we travel, the more we exchange resistant bacteria, passing on potentially dangerous strains to each other and, most importantly, “helping” them exchange resistance genes.

While some can afford to travel, others cannot afford new drugs: this means that they use only outdated antibiotics. Fair access to antibiotics is being talked about more and more, but so far, the situation has not changed greatly. But even in places where there are new drugs that have low resistance levels, some doctors still prefer to prescribe already familiar drugs they’re more familiar with, whose action fits into their experience, and not to resort to other antibiotics. Worryingly, some doctors openly say that sometimes they prescribe antibiotics regardless of the results of the bacteriological test too, simply because it seemed “more correct” to them.

Antibiotics are also quite often used in other areas: for instance, agriculture. At the very beginning of the antibiotic era, it turned out that adding small doses of antibiotics to animal food leads to an increase in animal weight gain of 20%! Moreover, antibiotics guarantee that fewer animals will die from infections, which can be especially important in intensive farming. Feed antibiotics have already been banned in many countries – from the EU to Latin American countries, but the level of resistance in food-producing animals is still extremely high, even in Europe (Figure 3).

Figure 3. Antimicrobial resistance prevalence of A) E. coli B) Salmonella C) Campylobacter in food producing animals to a range of antibiotics; 2009–2020. AMP, ampicillin; CAZ, ceftazidime; CHL, chloramphenicol; CIP, ciprofloxacin; CST, colistin; CTX, clavulanic acid; EFAS, European Food Safety Authority; FOX, cefoxitin; GEN, gentamicin; IPM, imipenem; NAL, nalidixic acid; PPS, point prevalence survey; STR, streptomycin; TET, tetracycline. Credit: Mulchandani R. et al, 2024 reproduced under a Creative Commons Attribution 4.0 International License.

Random mutations that prevent antibiotics from working effectively on bacteria are an important source of resistance that may go unnoticed until that bacterium comes up against that specific antibiotic. Consequently, such mutations can exist even before antibiotic treatments, but antibiotic use then selects for them and these mutations spread in bacterial populations. Natural occurrence of antibiotics also plays a role in this selection process. Back in the middle of the last century, it was shown that methicillin-resistant bacteria appeared before the introduction of the corresponding drugs into mass practice, and hedgehogs are responsible for this. Two β-lactam antibiotics were produced by the hedgehog dermatophyte Trichophyton erinacei (T. erinacei), a small fungus, that drove this selection process. Other species are actively involved in the spread of resistance too: there is evidence that resistance to polymyxins, one of which is the aforementioned colistin, is transmitted through the microbiome of flies, birds and dogs.

What to do?

The first thing that comes to mind when we hear about antibiotic resistance is a reduction in the consumption of antibiotics and strict control. Such control is already being implemented: now in many countries where, according to the law, antibiotics can only be bought in pharmacies with a doctor's prescription. The use of antibiotics in agriculture is also limited, and even in antibacterial treatment, new solutions are being proposed – for example, researchers destroyed bacteria on surgical implants to complete sterility using infrared light instead of antibiotics. It is also essential to educate healthcare professionals on proper antibiotic stewardship and prescribing practices, as well as to educate patients and improve their compliance.

But what to do with the fact that a number of bacteria already have resistance?

The obvious solution seems to be to search for new drugs and classes of antibiotics. Over the past decades, only a few antibacterial drugs have been approved – some of the recent ones being cefiderocol, darobactin and imipenem. In 2024, researchers from the University of Illinois announced the creation of a new drug from the macrolide group – lolamycin – which disrupts the transport system of bacteria. It is assumed that the new antibiotic will significantly slow down the development of resistance and, if it does not save us, then at least give us time. But all of these are drugs from existing classes, with certain characteristic features and a similar mechanism of action. Yes, if a drug acts in several ways at once, then resistance is less likely to develop, but it still exists.

No less important is the development of new and fast systems for detecting bacteria and identifying their resistance profiles. The faster a doctor can determine what kind of bacteria caused the infection and what specific drugs it is resistant to, the better the therapy is. One of the problems with resistance is that antibiotics are often prescribed based only on symptoms and clinical recommendations, without identifying the specific pathogen. The most modern resistance test systems require only an hour and a half to conduct a test versus more traditional culture-based methods, such as disk diffusion, that take 24 hours to days (especially if the target bacteria is a slow-growing anaerobes), but they are not widespread.

There is another option: changing the chemical nature of antibiotics so that they perform their task, but at the same time “look” different to the bacteria. This is how synthetic analogues of natural antibiotics appeared. This scheme is well-established but seems to have outlived its usefulness: we have already received almost everything that was possible.

Bacteriophage offer an alternative solution. These small viruses only infect bacteria, destroying them without affecting human cells. Yes, bacteria can also develop resistance to them, and quite quickly: but bacteriophages are not far behind, constantly mutating in an arms race with their hosts. However, there are also disadvantages: bacteriophages are quite difficult to produce on an industrial scale, and they also have certain problems with reproduction inside the organism they are designed to protect. In addition, they are species-specific, and the development of new phages for the treatment of infections is a long and maybe much too expensive process. This significantly hinders the spread of bacteriophage therapy.

The real “superbug” hasn't appeared yet. But the speed that resistance is developing is a little unsettling. Some years ago, artificial intelligence (AI) joined the study of antibiotics. Processing an array of information that would take a person tens of years takes AI a few days. It can screen molecules faster, finding among them those that can become the new penicillin. In 2020, with the use of AI, scientists were able to screen over 100 million molecules for antibiotic activity and identify a new molecule, halicin: a substance that exhibits activity against carbapenem-resistant Enterobacteriaceae and Mycobacterium tuberculosis. Another study in 2024 similarly found several compounds active against Acinetobacter baumannii. AI models are also used to predict the progression of infection and the spread of resistance. However, we are still a long way from actually solving the resistance problem using AI, if there is such a way at all.

What can we do now? Take antibiotics exactly as prescribed by a doctor, take cultures for drug sensitivity whenever possible, do not stop taking them halfway and do not share pills with others.