bacterial resistance
Resistance is something very characteristic of all living beings. At all times, we are resisting different things, the temperature of the environment, falls, cuts, diseases, the same atmospheric pressure, and the gravity exerted by the planet we live on. All these "resistances," which generally allow us to continue living, are the result of millions of years of evolution and adaptation since we were unicellular organisms until today. Nowadays, humans can resist all temperatures on the planet, achieving a life that was never imagined, even outside our planet, and although these are not "natural" resistances, we have made ourselves resistant to many things, but we are not the only ones. There are other organisms that have developed impressive resistances, and even though they are tiny, their resistances are enormous. Bacteria are among the most versatile organisms in the world, numbering in the billions and covering the vast majority of the world; there are bacteria that have developed to withstand extreme temperatures, extreme pH levels, and even extreme radiation levels, with a special mention to Deinococcus radiodurans, these are extremophilic bacteria, but these incredible resistances do not compare to bacterial resistance, which threatens the survival of our species, resistance to antibiotics.
Antibiotic-resistant bacteria, or superbugs as they have come to be known, are one of the most relevant public health issues and threaten to become an uncontrollable problem in the not-so-distant future. This resistance to antibiotics occurs through mutations in the bacteria that cause antibiotics to lose their effectiveness against them. There are many antibiotics with multiple mechanisms of action, such as streptomycin, an aminoglycoside antibiotic and one of the most used today, which works by binding to the bacterial ribosome, causing the production of truncated and defective proteins or even completely inhibiting their production, thus preventing the replication and overall action of the bacteria. [1] However, bacteria like Mycobacterium tuberculosis have already adapted to these actions, with specific mutations in genes like rsl, which codes for the ribosome; these modifications alter the ability of streptomycin to bind to the ribosome, rendering the antibiotic completely harmless to these bacteria. [2] There are several other examples of structural modifications, or in the membrane, or even the development of enzymatic mechanisms to neutralize antibiotics.
This image shows the evolution of bacterial resistance. These are antibiograms; what is done is placing these white discs containing different antibiotics in a massive culture of bacteria, then they grow and generate inhibition halos, the areas without bacteria observed on the left. But as can be seen in the right culture, the inhibition halos are much smaller than they were a few years ago.
The World Health Organization (WHO) has been warning for several years about the problem posed by antibiotic-resistant bacteria, even calling it “one of the greatest threats to global health.” There is a growing number of infections like pneumonia, gonorrhea, or tuberculosis that are becoming increasingly difficult and sometimes simply impossible to treat. Yet even when this problem seems to be a genuine threat to the survival of thousands of people, society does not seem to be aware of how thousands of people die every year from resistant infections. With the great availability of pharmaceuticals today, two main obstacles arise. The abuse of antibiotics and their misuse and the lack of development of new antibiotics. [3] Pharmacological development has concentrated heavily on innovation in drugs for cancer, cardiovascular problems, the generation of monoclonal antibodies, genetic problems, and personalized medicine, and all this is very good; there are increasingly more news like the Mexican scientist who managed to eradicate the human papillomavirus (HPV) in 29 women, completely freeing them from cervical cancer associated with this virus [4] it would be outrageous to say that something like this is bad, but not everything is simply due to kindness, as it has much to do with the return on investment. Pharmaceutical innovation is extremely extensive, both in terms of money and time, and since “some options” already exist, it is not often seen as profitable to generate new antibiotics but rather to continue developing the existing ones, which do not have the same effects and do not usually avoid resistances. Another representative of the WHO states, "The current situation is a dead end. It’s not that we don’t have new antibiotics; it’s just that we don’t have antibiotics from new families; we only have improvements on drugs we already use.” [3]
A report from the WHO's Global Antimicrobial Resistance and Use Surveillance System (GLASS) analyzed the rate of antibiotic resistance in relation to the coverage of analytical tests in each country, as well as trends since 2017, in addition to data on human consumption of these medications in at least 27 countries. What was revealed in this report were initially elevated resistance levels above 50% in bacteria causing sepsis in hospitals, such as Klebsiella pneumoniae. Hospital-related sepsis is a very dangerous infection, primarily present in recovering surgical patients who have compromised immune systems, making them susceptible to complications resulting from the infection. To treat these infections, last-resort antibiotics such as carbapenems are often employed, which are bactericidal antibiotics that work by inhibiting bacterial cell wall synthesis. They inhibit transpeptidation at the final stages of peptidoglycan synthesis, an essential polymer for the bacterial wall. The alteration of the wall activates autolytic enzymes that cause the destruction of the bacteria. [1,5] However, according to the report, 8% of sepsis cases caused by K. pneumoniae are resistant to this type of antibiotic, considerably increasing the risk of the infection. [5]
Common infections have also developed a trend towards increased resistance to treatments. More than 60% of the strains isolated from Neisseria gonorrhoeae, responsible for one of the most common sexually transmitted diseases, have shown resistance to one of the most used antibacterial drugs, ciprofloxacin, an antibiotic belonging to the fluoroquinolones, which acts by selectively inhibiting bacterial DNA gyrase, an enzyme participating in the folding of the DNA double helix, and which is fundamental for the correct three-dimensional structure of genetic material. [1,5] More than 20% of isolates of Escherichia coli, the most common infectious agent in urinary tract infections, were resistant to both first-line drugs (ampicillin and trimethoprim-sulfamethoxazole) and second-line treatments, which should be more targeted and powerful (fluoroquinolones). Dr. Tedros Adhanom Ghebreyesus, the Director-General of the WHO since 2017, stated the following regarding this issue, "Antimicrobial resistance erodes modern medicine and puts millions of lives at risk; to truly apprehend the magnitude of the global threat and organize an effective public health response against antibiotic resistance, we must multiply microbiological analyses and generate guaranteed quality data in all countries, not just the richest." [5] Due to insufficient coverage of analytical testing and a shortage of sufficiently equipped laboratories, especially in developing countries, it remains difficult to accurately interpret antibiotic resistance rates. To address this issue, the WHO plans to obtain evidence-based data through surveys in the short term; in the long term, the plan is based on generating systematic surveillance capacity, which would translate into implementing representative national surveys on the prevalence of these resistances, generating a new reference data set and trend data in the field that can be used to shape and issue policies and closely monitor interventions. [5]
The WHO has a list of these resistant bacteria, with the latest update in 2024, in which five combinations of pathogens and antibiotics have been removed from the original 2017 list and four new combinations have been added. Enterobacteria resistant to third-generation cephalosporins are listed in a separate group within the critical priority category, highlighting their morbidity and mortality burden and the necessity for specific interventions to address them, particularly in low- and middle-income countries. Here is the list of WHO's priority bacterial pathogens: [6]
Critical priority:
Carbapenem-resistant Acinetobacter baumannii
Third-generation cephalosporin-resistant enterobacteria
Carbapenem-resistant Enterobacterales
Rifampicin-resistant Mycobacterium tuberculosis.
High priority:
Fluoroquinolone-resistant Salmonella Typhi
Fluoroquinolone-resistant Shigella spp.
Vancomycin-resistant Enterococcus faecium
Carbapenem-resistant Pseudomonas aeruginosa
Fluoroquinolone-resistant non-typhoidal Salmonella
Neisseria gonorrhoeae resistant to third-generation cephalosporins and/or fluoroquinolones
Methicillin-resistant Staphylococcus aureus
Medium priority:
Group A streptococci resistant to macrolides
Macrolide-resistant Streptococcus pneumoniae
Ampicillin-resistant Haemophilus influenzae
Group B streptococci resistant to macrolides
In this list, there are too many relatively common microorganisms, and although not all their infections will be resistant, gradually the more resistant population will gain dominance over "common" bacteria, a perfect example of Darwinian evolution. The changes made since 2017 reflect the dynamics of antimicrobial resistance, which forces adaptations in interventions. In order to use this list as a tool worldwide, it must be adapted to national and regional contexts taking into account regional variations in the distribution of pathogens and the burden of resistances. For example, drug-resistant Mycoplasma genitalium, which is not included in the list, is becoming increasingly problematic in some parts of the world. [6]
This threat must be confronted; all countries must participate in the effort to combat it, enhancing their surveillance capacity and providing quality information, and the civil community must also act, starting by informing themselves and knowing the risk. If this is achieved, we can begin to lay the groundwork for an effective and scientifically sound action to tackle the emergence, spread, and prevalence of antibiotic-resistant bacteria, thus protecting the use of antimicrobial medications for future generations. Resisting is natural, and these bacteria are among the best evolutions we have, but their risk is too significant to continue ignoring; the next great pandemic could be the last.
References
1. Obando-Pachecoa P, del Carmen Suárez-Arrabalb M, Jesús Esparza Olcinac M. General overview of the main groups of antimicrobial drugs. Antibiotics [Internet]. Guia-abe.es. 2020 [cited 2025 Feb 12]. Available from: https://www.guia-abe.es/generalidades-descripcion-general-de-los-principales-grupos-de-farmacos-antimicrobianos-antibioticos-
2. Arráiz N, Bermúdez, Urdaneta B. Drug resistance in M. Tuberculosis: Molecular bases. Arch Venez Farmacol Ter [Internet]. 2005 [cited 2025 Feb 12];24(1):23–31. Available from: https://ve.scielo.org/scielo.php?script=sci_arttext&pid=S0798-02642005000100
3. Multidrug-resistant bacteria, the new threat [Internet]. https://www.cun.es. [cited 2025 Feb 12]. Available from: https://www.cun.es/en
5. WHO. A report highlights the increase in antibiotic resistance in bacterial infections affecting humans and the need to improve data on this matter [Internet]. Paho.org. 2022 [cited 2025 Feb 12]. Available from: https://www.paho.org/es/noticias/9-12-2022-informe-pone-relieve-aumento-resistencia-antibioticos-infecciones-bacterianas
6. WHO. The WHO updates the list of the most dangerous drug-resistant bacteria for human health [Internet]. Who.int. 2024 [cited 2025 Feb 12]. Available from: https://www.who.int/es/news/item/17-05-2024-who-updates-list-of-drug-resistant-bacteria-most-threatening-to-human-health"
Comments