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Superbugs: The Next Silent Pandemic

“A post-antibiotic era — in which common infections and minor injuries can kill — far from being an apocalyptic fantasy, is instead a very real possibility for the twenty-first century,” Keiji Fukuda, WHO assistant director-general for health security.

The control of bacterial infections is of crucial importance for modern medicine, which is built on antibiotics. The fortuitous discovery of penicillin by Alexander Fleming in 1928 sparked a golden era of antibiotic discovery that peaked in the mid-1950s with the development of half of the antibiotics still used today (Tan & Tatsumura, 2015). From the 1940s through the 1960s, the majority of antibacterial agents or derivatives were isolated from natural sources. Most of these compounds come from a once promising discovery platform established by Selman Waksman in the 1940s (Schatz et al., 2005). This was a relatively straightforward development platform, consisting of searching for actinomycetes from the soil, a category of microorganisms related to bacteria, capable of inhibiting the growth of other microorganisms. This fostered a thorough search for antimicrobial drugs to combat disease, a quest rendered urgent by the looming outbreak of war (Selman Waksman and Antibiotics, 2005). This platform pioneered the discovery of streptomycin, the first effective therapy for tuberculosis, and was eventually exploited by pharmaceutical companies over the next 20 years, allowing the discovery of numerous other families or classes of antibiotics. With increasing challenges to find new unknown or unrelated molecules, the pipeline eventually dried up and this strategy was abandoned (Lewis, 2013).

Figure 1 - Humanity has been pushing bacteria to become resistant for almost 60 years, and the global wave of resistance has rendered current therapies inadequate (The antibiotics resistance crisis', 2017).

After the Waksman platform, semi-synthetic and fully synthetic antibiotic platforms emerged allowing for the introduction of new active substances and important families of antibiotics. Moreover, fully synthetic production has made it possible to manufacture antibiotics on an industrial scale (Ribeiro da Cunha et al., 2019). The advent of antibiotics for therapeutic purposes was perhaps the most notable medical milestone of the 20th century. Antibiotics revolutionized modern medicine in less than a century and increased the average human life expectancy by more than two decades (Katz & Baltz, 2016). However, following the victories of the antibiotic golden age, the rate of antibiotic discovery has slowed, resulting in the emergence of class and drug resistant mechanisms, as well as the advent of superbugs. Superbugs are bacteria strains that have developed resistance to most known antibiotics. This translates to a significant decrease in the treatment effectiveness of the antibiotic arsenal and reintroduces the infectious disease challenge (Hutchings et al., 2019).

From Essential to Marginal: The Doom of Antibiotic Discovery

Since the discovery of penicillin, nearly 150 new antibiotics from 31 different classes have been developed, saving millions of lives worldwide (Drexler, 2019). Infections that used to be fatal were no longer feared, and today procedures such as open-heart surgery and cancer chemotherapy, organ transplants, and caesarean births have become a reality (Drexler, 2019). However, misuse of these essential drugs has led to an alarming rise in antimicrobial resistance (AMR) and rendered numerous formerly curable diseases virtually untreatable (Prescott, 2014). Surprisingly, when penicillin reached the commercial market in early 1945, Fleming predicted the end of his great triumph. Fleming warned in his Nobel acceptance speech that the high public demand for antibiotics would lead to an "era of abuse" that would ultimately end in resistance emergence: “It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body. The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant.” (Fleming, 1945).

Figure 2 - The discovery of penicillin by Alexander Fleming was a fortuitous accident, resulting from the unintended contamination of a petri dish (Stuttle, 2018).

Five years later, Staphylococcus aureus, the bacterium Fleming originally used to illustrate the remarkable potency of penicillin, became the first strain to exhibit widespread antibiotic resistance (Chambers & DeLeo, 2009; Shaffer, 2013). Today, nearly all of the bacteria that plague mankind are, to varying degrees, resistant to the drugs designed to combat them, threatening the very foundations of modern medicine. What were once considered simple and easily treatable infections are now managed with multiple rounds of potent and sometimes toxic drugs that often require lengthy hospital stays, more medical follow-ups, and expensive and toxic alternatives (Antimicrobial Resistance Questions and Answers, 2022). AMR has emerged as one of the most serious public health problems of the 21st century, posing a threat to the effective prevention and treatment of an increasing number of infections brought on not only by resistant bacteria but also by parasites, viruses, and fungi that can no longer be treated with conventional therapies.

A Global Health Crisis: Rising to the Era of Resistance

Antimicrobial resistance (AMR) develops when bacteria, viruses, fungi, and parasites evolve over time and become insensitive to treatment, rendering infections challenging to cure and raising the risk of disease transmission, serious illness, and death (Antimicrobial Resistance, 2021). It is noteworthy that after penicillin, the discovery of each new generation of antibiotics quickly followed the same trend. The advent and spread of drug-resistant bacteria with novel resistance mechanisms currently places humanity's capacity to cure common infections at jeopardy. Of particular concern is the global prevalence of multi- and pan-resistant bacteria (also known as superbugs), which cause infections unresponsive to most or all existing antibiotic pipelines, respectively (Magiorakos et al., 2012). Fleming's nightmarish vision has now become real. Antibiotic resistance in bacteria, either through chromosomal mutation or horizontal gene transfer (transfer of DNA between different genomes, i.e. transfer of genetic material to another organism that is not its descendant), is a naturally occurring phenomenon that can be observed regardless of human involvement (D’Costa et al., 2011; Wellington et al., 2013). However, in 2001, the European Surveillance of Antimicrobial Consumption (ESAC) examined AMR variants in selected bacteria and established a definite correlation between resistance and antimicrobial usage in Europe. This was especially notable for Streptococcus pneumoniae, the causative agent of pneumonia and meningitis, which revealed higher rates of antibiotic resistance in Southern and Eastern Europe, including France, Spain, Portugal, and Slovenia, where antibiotic use is higher than in northern European countries (Goossens et al., 2005).

Figure 3 - The evolution of antibiotic resistance in bacteria ("Mutation and Selection", n.d.).

A potential contributor to growing antibiotic resistance is excessive prescription and inadequate administration regimens (Ventola, 2015). Remarkably, a study conducted in the United States reviewing antibiotic prescription data from 2010 and 2011 found that about 30% of prescriptions for oral antibiotics were excessive (Fleming-Dutra et al., 2016). According to the World Health Organization (WHO), this concern is compounded by the ability to legally obtain antibiotics over the counter in 19 European countries and even online without a prescription in five countries. The easy access to antibiotics is a major contributor to overuse, largely exacerbating the current problem of antibiotic resistance. In addition, WHO's most recent survey regarding antimicrobial resistance (AMR) found that only two-thirds of people in 14 countries in the WHO European Region received their last antibiotic treatment through a doctor's prescription (1 in 3 Use Antibiotics without Prescription, 2022). Additionally, 50% of respondents across participating countries said they had used antibiotics in the past year, with a staggering 61% of respondents unaware that antibiotics do not work against viruses, and wrongly believing that they work against the common cold. It is also important to point out that the agricultural sector has a substantial impact on the development of antibiotic resistance. A growing population, especially in developing countries, demands a greater amount of animal protein production. This leads to intensive farming practices where antibiotics have become commonplace for animal production not only to improve animal health and well-being but also to enhance growth rates so that population demands are met (Manyi-Loh et al., 2018). Therefore, easy access to antibiotics, misuse and overuse are probably the underlying forces that have contributed most to the current antibiotic resistance crisis.

Superbugs and The Post-Antibiotic Era

While the inappropriate and overuse of antibiotics are major drivers of the antibiotic resistance crisis, the pharmaceutical industry's failure to develop new antibiotics due to limited financial incentives and onerous regulatory requirements also contributes significantly to this problem (Gould & Bal, 2013; Piddock, 2012). The current development of new antibacterial treatments is not enough to address the growing threat of antibiotic resistance. Superbugs are predicted to overtake cancer as the leading cause of death worldwide by 2050, with antimicrobial resistance claiming 10 million deaths annually (Antibiotic Resistance, 2020). In an effort to coordinate and steer research for discovering novel therapies, the WHO released in 2017 a list of diseases for which new antimicrobial advances are urgently required. The priority status was assigned to the ESKAPE pathogens, a group of six bacteria strains that cause life-threatening infections in hospital and exhibit multidrug resistance, namely Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species (Davies, 2017; Rice, 2008). The COVID-19 pandemic compounded this astonishingly high rate of resistance, with a global response to the pandemic spurring a significant increase in the usage of disinfectants, detergents, and antibiotics (Nayak & Parshionikar, 2021). Many infectious diseases have made a remarkable return. Syphilis, gonorrhea and tuberculosis are all making a comeback, and the emergence of HIV, hepatitis C and severe acute respiratory syndrome (SARS) has been sobering (Nelson, 2003).

Figure 4 - Death from AMR in comparison to other diseases by 2050 (McCarthy, 2015).

A critical strategy in the battle against AMR is the hunt for new antibiotic classes. Since the 1980s, new antibiotics have been either improved or modified versions of already approved drugs. WHO warns of a lack of new discoveries, claiming that the current pipeline of antibiotics is stagnant and falls far short of global demands (WHO, 2021a). Only 12 antibiotics have been licensed since 2017, and 10 of these are from existing classes with proven AMR mechanisms. New drug development is hampered by the lengthy approval process, which today takes about 10 to 15 years to bring an antibiotic candidate to the market, high prices, and dismal success rates, with only one in 30 candidates for new classes of antibiotics reaching patients. Only 6 out of the 27 drugs in the clinical pipeline targeting priority infections meet at least one of the WHO's innovation criteria (WHO, 2021b). The small number of novel antibiotics entering the market is quickly being undermined by a lack of innovation. Moreover, resistance to most novel drugs is often detected 2-3 years after market launch. To cope with the rapid development of AMR, diversity and innovation are the cornerstones. Antibiotic discovery and development must address antibiotic resistance in both existing and new compounds.

It Takes a Village to Fight Antimicrobial Resistance

As AMR interfaces with human, animal and environmental health, it is vital that all sectors and stakeholders work more closely together to address it. Such collaboration is encouraged by the One Health initiative (Velazquez-Meza et al., 2022). For instance, if antibiotic overuse persisted for intensive farming, antibiotics stewardship, that is, attempts to assess and improve the way antibiotics are prescribed by physicians and used by patients would be rather scarce (WHO, 2019). Instead, a multi-faceted, interdisciplinary, and unified approach to health that involves many sectors and stakeholders in the design and implementation of programs, policies, legislation, and research is highly desirable (Laxminarayan et al., 2013; WHO, 2014). Furthermore, increased investment in research and development of innovative antimicrobial drugs, vaccines, and diagnostic tools is mandatory. Companies often interrupt drug development for several years in hopes of securing funding to resume development at later stages or to have the product licensed by another company (WHO, 2021b). Many companies file for bankruptcy.

Figure 5 - One Health aims at achieving optimal health outcomes recognizing the interconnection between people, animals, plants, and their shared environment (UNEP, 2021).

While the COVID-19 pandemic has hampered research, delayed clinical trials and diverted investor attention, it has also shown that strong partnerships between the public and private sectors in academia, industry and public health can be fostered to support the advancement of research and clinical trials in the face of a global public health crisis (Druedahl et al., 2021). Indeed, in response to the grim warnings and rapid exit from the antibiotic’s domain by companies like AstraZeneca, Roche, and Eli Lilly, a slew of programs have been launched to enhance research and boost antibiotic production. The Infectious Disease Society of America's (IDSA) 10 x '20 initiative, which intended to develop 10 novel systemic antimicrobials between 2010 and 2020, and the Innovative Medicines effort's New Drugs for Bad Bugs program have been established in this respect. These initiatives aimed at a global commitment to build a research and development company capable of producing innovative antimicrobials, with the ultimate goal of bolstering the fight against AMR at all stages - from basic research and drug discovery through clinical development and responsible use of antibiotics. Importantly, these economic incentives have also allowed smaller biotech companies to enter the market. Notably, IDSA's 10 x '20 program was a success with around 14 drugs approved in the US, exceeding the projected goal (Megget, 2021) .Additionally, the Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X), a global public-private partnership formed in 2016, has committed $500 million to fund the development of innovative drugs and rapid diagnostics to combat AMR (Robinson & Infante, 2022). Later, the launch of the Antimicrobial Resistance Multi Partner Trust Fund (AMR MPTF), the Global Antibiotic Research and Development Partnership (GARDP), or the AMR Action Fund, to mention just a few initiatives, have also helped to alleviate significant financial constraints (Dall, 2023; WHO, 2022, 2023). Such collaborative initiatives are urgently needed to find long-term solutions and expand the antibiotics pipeline, particularly in low-resource countries, which are the most afflicted by AMR.

Importantly, innovative techniques, such as bacteriophage-based vaccinations, are emerging to tackle antibiotic resistance and avert a crisis. These vaccines, as the name implies, are based on bacteriophages, a sort of virus capable of destroying bacteria. Despite the fact that bacteriophage therapy first appeared almost a century ago, its use ultimately ceased with the arrival of antibiotics. However, due to bacteriophage selectivity for a particular bacterium species, monotherapy in clinical settings may be insufficient. A correct match between bacteria and bacteriophages (virus) is a crucial factor in such a therapy. Therefore, even while bacteriophages can help battle antibiotic-induced AMR, a complete fulfillment of therapeutic needs typically calls for a bacteriophage cocktail therapy to widen the therapeutical range of action (Ling et al., 2022). In addition, the advent of nanotechnology has also opened up the possibility of creating nanoparticles - microscopic spheres small enough to act at the cellular level - of inorganic origin such as silica or other metals. In a synergistic antimicrobial relationship, the use of antibiotics bound to metal nanoparticles as bactericides can be highly effective in treating multidrug-resistant bacteria. This is due to the fact that while bacteria have evolved mechanisms to evade common antibiotics, this is not the case for metal nanoparticles, which are a completely new concept for bacteria and hence not recognized as a threat (Dove et. al, 2023).

Figure 6 - Nanoparticles emerged as a great alternative to tackle multidrug-resistant bacteria ((Gao & Zhang, 2021).


Reports of the spread of superbugs has skyrocketed in recent years. However, given the potentially disastrous nature of this situation, it may come as a surprise that policymakers have largely disregarded it. We are in an arms race with resistant microorganisms and we are losing it. One should consider a future where routine surgery or chemotherapy would be considered too dangerous due to a lack of drugs to prevent or treat bacterial infections. If researchers do not discover new antibiotics and drugs, modern medicine will be wiped out. Experts have long understood that considerably greater incentives for research and development are required to avoid this scenario. The speed and success of innovation is considerably below what is required for safeguarding modern medicine's achievements against ancient but re-emerging catastrophic diseases. As a result, superbugs continue to proliferate, posing a huge threat to global health in the shape of an antibiotic-resistant pandemic. In light of this, quick action is essential to avert a worldwide health crisis. In order to speed up and expand the pipeline for antibiotics, governments and the private sector urgently need to make coordinated investments in scientific research and development. At the same time, nations should cooperate to find long-term solutions through innovation so that a sustainable antibiotic ecosystem is built.

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Maria Inês Marreiros

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