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Antimicrobial Resistance 101: Solutions to Antimicrobial Resistance

Foreword


Antibiotics were a major breakthrough in science. Microorganisms such as viruses, bacteria, fungi, and more can be treated by antibiotics relatively simply. Upon the introduction of antibiotics, previously deadly illnesses could now be treated with incredible efficacy. However, the pathogens targeted by the first antibiotics soon started to become resistant.


Antimicrobial resistance is one of the biggest problems in modern medicine. There is evidence of bacterial infections evolving to become resistant to the complete arsenal of antibiotics. As a result, people are increasingly dying from simple infections that would not have been dangerous a few years ago. Because the situation is only going to get worse in the coming decades, it is time to think about alternatives.


The Antimicrobial Resistance 101 series will be mainly divided into the following chapters:






5. Antimicrobial Resistance 101: Solutions to Antimicrobial Resistance


6. Antimicrobial Resistance 101: Antimicrobial Resistance in the Future


Antimicrobial Resistance 101: Solutions to Antimicrobial Resistance


This series has covered many elements of antimicrobial resistance. While researchers and experts emphasise that antimicrobial resistance is a growing problem, some treatments could be promising alternatives to antimicrobials. Like other articles in this series, the main focus will be on antibiotics (medication against bacteria), though some alternatives to antivirals and antifungals will be discussed as well. The article will also explore antibodies, a type of protein that the body makes by itself, which can be harnessed and used to fight a number of infections.


Every pathogen creates proteins that are specific to themselves. Some of these are found on the outside of the pathogen, that is, on the membrane of a bacterium, fungus or virus (Bonilla & Oettgen, 2010). Because they are unique, and therefore different to any other protein found in a human body, one’s immune cells may recognise them as foreign, and start to attack cells, or viruses, that express these proteins. These proteins are called antigens (Bonilla & Oettgen, 2010). The most potent part of the human immune system is the adaptive immune system, that produces antibodies. These are small, and relatively simple molecules that are expressed for a very specific antigen (Bonilla & Oettgen, 2010). The immune cells of any single person can create vast amounts of different antibodies, each of which recognises and attaches to a single antigen. Once attached, these antibodies inhibit the functions of the cell attacked, including replication. Alternatively, when other immune cells find a bacterium to which many antibodies are bound, the immune cells will recognise them as dangerous and kill them. Antibodies are therefore key in clearing infections.


Figure 1: Antibodies attacking, and neutralizing, a virus (Zoppi, 2021).

When a patient is infected with a pathogen for the first time, the immune system will recognise an antigen it has never seen before. It, therefore, has to sample this antigen and bring it to B-cells, a type of immune cell responsible for the production of antibodies, which takes time. Afterwards, memory cells are developed, which, when activated, directly produce enormous amounts of such antibodies specific to the antigen. The second time that a patient is infected, immune cells only have to travel to the memory cells and activate them, which results in an infection being cleared much more rapidly. This is when one has achieved immunity (Bonilla & Oettgen, 2010).


This process is exactly how vaccines work. By introducing only a specific antigen, the body will recognise that antigen and develop memory cells, offering protection from any future infections from the pathogen. This vaccine does not contain the parts of the virus or bacterium that make one ill (Bonilla & Oettgen, 2010). It, therefore, brings no risk of any disease or infection, although adverse effects may develop as a result of the immune system being activated. While these effects can, on rare occasions, be incredibly serious, mostly they are relatively minor, and may include a fever, a headache or swollen lymph nodes (Center for Disease Control and Prevention, 2022).



Figure 2: Antibody levels after vaccination. The grey line is the antibody level for people that have not been vaccinated with a vaccine for SARS-CoV2. The green, blue and red lines show antibody levels after vaccination. Vaccination drastically increases antibody levels (Wheeler et al., 2021).

Such vaccines work predominantly as a preventative mechanism for infection. Once vaccinated, the body will quickly respond so that the pathogen does not have any time to infect the person or cause serious disease. In other words, vaccines are great preventive methods, though as a curative method, not so much. That is, for patients actively suffering from an infection, vaccination will typically not be helpful, because the immune system is already responding; essentially, by that point, it is too late. Antibodies themselves, however, may be used as a curative treatment. That is, they may be used for patients that are already infected and are currently fighting the disease. After identification of the microbe responsible for the infection, clinicians need to identify the antigen for which antibodies would be specific. Then, the clinician could inject the patient with such antibodies that will directly attack the pathogen. Because the body is not making the antibodies itself, in this case, this therapy is termed passive antibody treatment (Jahanshahlu & Rezaei, 2020).


Alternatives to Antibiotics

Many different alternatives to antibiotics have been identified over the years. The therapies that have attracted the most attention include nanotechnology and bacteriophages. These are not the only two possible alternatives to antibiotics, however. Bacteria are incredibly diverse, given that they have been evolving for the past 3 billion years (Alegado & King, 2014), and as a result, many bacteria have evolved to fight each other, similarly to how ants may fight other ants for territory (Moffett, 2019). Therefore, if the strain of infection has been identified, clinicians may prescribe ingestion of the natural enemies of the bacteria that are causing the infection. Bacteria used in this way are called probiotics and are studied intensely. Although many claims are circulating on the positive effects of probiotics, for now, the majority is simple speculation, and hard evidence is hard to come by (Bermudez-Brito et al., 2012). Additionally, because a large range of species may cause infections, the effectiveness of probiotic treatment differs per infection. The fact that one species is a suitable probiotic for a given infection, does not mean it is suitable for any infections (Bermudez-Brito et al., 2012). An important benefit of probiotics is that they rarely have negative side effects. Prebiotics, while sounding similar to sounds similar to probiotics, are a very different thing. Probiotics are living bacteria that inhibit the growth of other bacteria. Probiotics have the same function, but are not alive (Matzaras et al., 2022).


Figure 3: Numerous bacteria can be used as probiotics. This is an overview of the six most common probiotics (Bridge Chiropractic, n.d.).

Bacteria have many natural enemies. The bacteriophage is among them. These are viruses that are specific to bacteria and therefore do not infect humans or any other multicellular organism. They function similarly to other viruses, including the ones that may cause a viral infection in humans. Phages infect and hijack a bacterium, forcing it to replicate many new viruses, which in turn infect new bacteria. Amazingly, these bacteriophages are incredibly specific and relatively easy to synthesise. They are so specific that they often infect a very restricted group of bacteria, making it easy to target an infection. Additionally, because bacteriophages cannot infect humans, the adverse effects are minimal.


In contrast to many other alternatives to antibiotics, including prebiotics and probiotics, bacteriophages have been studied extensively, also in clinical cases. In terms of application, their options are numerous. Ingestion works just as well as an intravenous injection (directly in the blood). Phages have been tested for a wide range of infections, yielding promising results. However promising phages are as an alternative therapy for antibiotics, these viruses cannot be used for any bacterial infection. After all, they cannot infect multicellular cells, and thus bacteria that live within the cells of a human cannot be targeted by phages (Duckworth & Gulig, 2002). Although some bacteria have been shown to grow resistant to bacteriophages, bacteriophages too undergo evolution (Oechslin, 2018). These are two mutating biological agents, each of which is subjected to mutations, and thereby natural selection and evolution. When a bacterium grows resistant to the phage, the phage may mutate in such a way that it targets the bacteria in a novel way, so that the bacterium is again, susceptible to the phage (Oechslin, 2018).


Figure 4: This is how most viruses are displayed in media. However, this specific structure is exclusive for bacteriophages, that cannot infect human cells (Asanga, 2022).

Alternatives to Antivirals

Besides the development of new antiviral drugs, excitement has emerged concerning nanomaterials as alternatives to antivirals. Nanotechnology is a very broad term, constituting practically any piece of technology that is incredibly small. The Pfizer and the Moderna vaccines against COVID-19 are both examples of such nanotechnology. These are custom-made viral particles that are vectors, meaning that they carry cargo. A small piece of the SARS-CoV2 virus’ mRNA can be found within these particles. Once inside a cell, these unload their mRNA so that the infected cell produces the antigen of the virus. By doing so, the antigens by which the virus can be recognised are produced throughout one’s body, without the virus actually being present, as the vector does not hold enough of the virus’ genes to make someone very ill. Besides the adverse effect of someone feeling under the weather as their immune system is activated, the vaccine is harmless, while training the same immune system on recognising the virus. If this person is later infected by the virus, the immune system can attack the virus much more rapidly and effectively, often resulting in a minor, rather than a serious infection (Mascellino et al., 2021).


This is a preventative therapy, generally meant to prevent severe infection of a virus. As treatment for a patient infected with a virus, vaccinations are typically less useful, as their immune system is already activated. An additional vaccine, therefore, does not contribute at this point. That does not mean to say that no single nanotechnology can be used as a curative therapy. The vast majority of the proposed techniques are still only studied in the academic setting, and can therefore not be applied outside of the lab, though results are promising. There are many different proposed technologies, each functioning in vastly different ways. Some are synthesised in such a way that they act as decoys for cell membranes; thereby occupying all the viruses so that they cannot infect cells any further. Another example is a particle that breaks apart the membrane of a virus, thereby killing it. A difficulty with such therapies is, however, that viruses mutate and thereby change their genetic and structural makeup very rapidly (Peplow, 2021).


Figure 5: In this artist’s impression, a DNA shell traps a virus to stop it from interacting with host cells (Peplow, 2021).

Alternatives to Antifungals

Fungi are incredibly interesting organisms. They are significantly more complex than bacteria and viruses and are much more closely related to animals than the former two. They are under-researched, especially in comparison with other microorganisms, and because they are closer to the complex biology that makes up humans, it is difficult to treat fungi without any adverse effects (Mehra et al., 2012). Because the available therapeutic arsenal against fungi is already comparatively small, and the prevalence of resistant fungi is increasing, more drugs, and specifically alternatives to the current antifungals, are necessary. In recent decades, many proteins have been identified to have antifungal activity. Many of these have species-specific activity, and together they would form a list too long for this article. One specific group that seems to be promising are small positively charged (or, cationic,) molecules that target the fungal cell membrane. These have been shown to be highly effective, even on fungal species known to be resistant to current drugs. Additionally, because some of them are produced by the human immune system naturally, the adverse effects are often minimal (Mehra et al., 2012). Experts warn, however, to not prescribe these treatments too easily, so that resistance will not emerge as rapidly. Instead, researchers suggest using these drugs alongside current therapies (Mehra et al., 2012). Experts agree that although many such components have been identified, the mechanisms by which they work have not been elucidated extensively.


All in all, antimicrobial resistance is a growing problem with serious consequences. Though this problem has been known for many years, alternatives to antimicrobials are still heavily researched and rarely applied in the clinic. Alternatives have, however, proven to be serious options. Though nanotechnology specifically, sounds very science-fiction-like, it is becoming a real possible treatment, just like using viruses to kill bacteria and stop infections. As more and more research is done on these techniques, the possibility of their applications continues to grow.



Bibliographical References

Alegado, R. A., & King, N. (2014). Bacterial Influences on Animal Origins. Cold Spring Harbor Perspectives in Biology, 6(11), a016162–a016162. https://doi.org/10.1101/cshperspect.a016162


Bermudez-Brito, M., Plaza-Díaz, J., Muñoz-Quezada, S., Gómez-Llorente, C., & Gil, A. (2012). Probiotic Mechanisms of Action. Annals of Nutrition and Metabolism, 61(2), 160–174. https://doi.org/10.1159/000342079


Bonilla, F. A., & Oettgen, H. C. (2010). Adaptive immunity. Journal of Allergy and Clinical Immunology, 125(2), S33–S40. https://doi.org/10.1016/j.jaci.2009.09.017


Center for Disease Control and Prevention. (2022). Vaccines. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/expect/after.html


Duckworth, D. H., & Gulig, P. A. (2002). Bacteriophages. BioDrugs, 16(1), 57–62. https://doi.org/10.2165/00063030-200216010-00006


Jahanshahlu, L., & Rezaei, N. (2020). Monoclonal antibody as a potential anti-COVID-19. Biomedicine & Pharmacotherapy, 129, 110337. https://doi.org/10.1016/j.biopha.2020.110337


Mascellino, M. T., Di Timoteo, F., De Angelis, M., & Oliva, A. (2021). Overview of the Main Anti-SARS-CoV-2 Vaccines: Mechanism of Action, Efficacy and Safety. Infection and Drug Resistance, Volume 14, 3459–3476. https://doi.org/10.2147/IDR.S315727


Matzaras, R., Nikopoulou, A., Protonotariou, E., & Christaki, E. (2022). Gut Microbiota Modulation and Prevention of Dysbiosis as an Alternative Approach to Antimicrobial Resistance: A Narrative Review. The Yale Journal of Biology and Medicine, 95(4), 479–494. http://www.ncbi.nlm.nih.gov/pubmed/36568836


Mehra, T., Köberle, M., Braunsdorf, C., Mailänder-Sanchez, D., Borelli, C., & Schaller, M. (2012). Alternative approaches to antifungal therapies. Experimental Dermatology, 21(10), 778–782. https://doi.org/10.1111/exd.12004


Moffett, M. W. (2019). When It Comes to Waging War, Ants and Humans Have a Lot in Common. https://www.smithsonianmag.com/science-nature/when-it-comes-waging-war-ants-humans-have-lot-common-180972169/


Oechslin, F. (2018). Resistance Development to Bacteriophages Occurring during Bacteriophage Therapy. Viruses, 10(7), 351. https://doi.org/10.3390/v10070351


Peplow, M. (2021). Nanotechnology offers alternative ways to fight COVID-19 pandemic with antivirals. Nature Biotechnology, 39(10), 1172–1174. https://doi.org/10.1038/s41587-021-01085-1

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