By Tanjim Sayeeda
Since Fleming’s discovery of penicillin in 1928, antibiotics have saved millions from infectious diseases (Rosenblatt-Farrell, 2009). However, as antibiotic use became rampant, bacteria developed defences against the drugs, rendering antibiotics useless and giving rise to antibiotic resistant bacteria (ARB), notoriously named “superbugs” (McCarthy, 2019). As ARB is responsible for 23,000 deaths in the US and European Union per year, the fear for global health rises as it becomes apparent that a post-antibiotic era may be no different to the pre-antibiotic era – when there was no treatment for infectious diseases and when minor injuries could warrant death. However, WHO and other global health organisations recognise and prioritise the threat of antibiotic resistance and are taking appropriate measures to counter the problem (Subramaniam and Girish, 2020).
Ironically, the aggressor for the antibiotic resistance crisis appears to be the once holy grail for treating infections- antibiotics themselves. The overuse and misuse of antibiotics are killing susceptible bacteria while ARB are left to proliferate and pass antibiotic resistant genes to subsequent generations (Shallcross and Davies, 2014). ARB also poses a huge risk to medicine and agriculture. Modern medicine’s achievements may be undermined, as medical procedures involving immunosuppression, such as organ transplantations, caesarean surgery, and chemotherapy, will be dangerous to perform without effective treatment for potential infections. Antibiotics are also used to treat livestock and crops to promote growth and increase yield of the product, but treating farm animals may cause ARB to thrive and thus be transmitted to humans through meat consumption, resulting in life-threatening infections (Kumar et al., 2005).
The economic burden will increase for both individuals and healthcare services, as more patients are admitted to hospitals due to infections by ARB such as tuberculosis, pneumonia and food-borne diseases. Expensive second and third line antibiotics will be necessary for treatment, meaning longer hospital stays and higher medical costs. Those in third world countries are at a greater risk of not being treated due to their having restricted access to third and second line treatments (Prestinaci, Pezzotti and Pantosti, 2015).
Unfortunately, the number of superbugs that are resistant to multiple antibiotics have already begun to increase, and they are currently winning the race against innovations to break antibiotic resistance. An infamous superbug – Methicillin-Resistant Staphylococcus aureus (MRSA) is a strain of Staphylococcus aureus (S. aureus), a group of bacteria responsible for skin infections, sepsis and fatal pneumonia. S. aureus infections were well controlled during the early days of penicillin. However, penicillin overuse gave rise to a resistant strain which produced penicillinases that hydrolyse penicillin’s β-lactam ring. Scientists developed methicillin- a semisynthetic penicillin incapable of being hydrolysed. However, methicillin was only effective for two years until resistance was once again developed in the MRSA strain. MRSA resistance is due to a mecA gene encoding for the penicillin-binding protein 2A which has a lower affinity for β-lactam drugs and thus avoids the uptake of antibiotics that would otherwise disrupt cell wall biosynthesis, and lead to lysis and death (Guo et al., 2020).
Other superbugs like Salmonella enterica, which cause infection through ingestion of contaminated food and water, produce enzymes like beta lactamase that hydrolyse antibiotics, consequently deactivating them before any damage can be done (Aljindan and Alkharsah, 2020). Escherichia coli contains strains responsible for diarrhoea and kidney failure, which can protect against a type of antibiotics called fluoroquinolones that inactivate the enzymes DNA topoisomerase VI and DNA gyrase thereby preventing DNA replication and transcription in bacteria, resulting in bacterial cell death (Alt et al., 2011).
The cause of antibiotic resistance is both microbial and human. The process of bacterial selection to counter the effectiveness of antibiotics by producing resistant strains did not begin with penicillin application in the 1940s, but is in fact a natural phenomenon in the microbial world. Microbes produce antimicrobial compounds as a defence mechanism against competing microbes (Clardy, Fischbach and Currie, 2009). Furthermore, antibiotic resistance genes could also have arisen as a result of random mutations that became inherited by subsequent generations due to the repeated induction of natural selection caused by the overuse of antibiotics. Another way bacteria become resistant is through mobile genetic elements like plasmids that can be transferred between non-related bacteria in a process called horizontal gene transfer (HGT).
Clinical practice can also contribute to the issue of antibiotic resistance in hospitals. Injecting broad-spectrum antibiotics to patients without specific symptoms can cause benign commensals to die and pathogenic bacteria to proliferate in the new competition-free environment. Benign commensals protect from infections by creating competition against pathogenic microbes. If hands are not washed diligently, healthcare workers unwittingly carry antibiotic resistant bacteria to other patients, that potentially results in lethal infections to already immunocompromised patients (Subramaniam and Girish, 2020).
The current conundrum is the necessity for new treatments juxtaposed with the reluctance to develop them, so antibiotic resistance does not escalate irreparably (Conly and Johnston, 2005). Future approaches to tackle the crisis may look to genetic engineering. Bacteria have an innate mechanism- CRISPR-Cas9, which recognises and removes foreign DNA as protection against parasitic elements like bacteriophages. If CRISPR-Cas9 is manipulated, plasmids that are carrying resistant genes can be removed; HGT-acquired antibiotic resistance could be prevented. Moreover, inappropriate use of antibiotics in the clinic are driving resistance in hospital settings. If clinicians can definitively answer whether patients have bacterial infections, broad-spectrum antibiotics can be abandoned, but rapid diagnostic tools would be necessary (Subramaniam and Girish, 2020). Cartridge based nucleic acid amplification tests that diagnose tuberculosis are showing promising results for the future of microbial diagnostics (Sahana, Prabhu and Saldanha, 2017). In short, winning the war against antibiotic resistance is very possible but relies heavily on the de-escalation and cautionary use of antibiotics moving forward.
Rosenblatt-Farrell, N. (2009) The Landscape of Antibiotic Resistance. Environmental Health Perspectives. 117 (6), A244-A250. Available from: https://search.datacite.org/works/10.1289/ehp.117-a244. Available from: doi: 10.1289/ehp.117-a244.
McCarthy, M. (2019) Superbugs. Penguin Publishing Group.
Subramaniam, G. & Girish, M. (2020) Antibiotic Resistance — A Cause for Reemergence of Infections. Indian Journal of Pediatrics. Available from: https://search.datacite.org/works/10.1007/s12098-019-03180-3. Available from: doi: 10.1007/s12098-019-03180-3.
Shallcross, L. J. & Davies, D. S. C. (2014) Antibiotic overuse: a key driver of antimicrobial resistance. British Journal of General Practice. 64 (629), 604-605. Available from: https://search.datacite.org/works/10.3399/bjgp14x682561. Available from: doi: 10.3399/bjgp14x682561.
Kumar, K., C. Gupta, S., Chander, Y. & Singh, A. K. (2005) Antibiotic Use in Agriculture and Its Impact on the Terrestrial Environment. In: Anonymous Advances in Agronomy. San Diego, Elsevier Science & Technology. pp. 1-54.
Prestinaci, F., Pezzotti, P. & Pantosti, A. (2015) Antimicrobial resistance: a global multifaceted phenomenon. Pathogens and Global Health. 109 (7), 309-318. Available from: http://www.tandfonline.com/doi/abs/10.1179/2047773215Y.0000000030. Available from: doi: 10.1179/2047773215Y.0000000030.
Guo, Y., Song, G., Sun, M., Wang, J. & Wang, Y. (2020) Prevalence and Therapies of Antibiotic-Resistance in Staphylococcus aureus. Frontiers in Cellular and Infection Microbiology. 10 107. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32257966. Available from: doi: 10.3389/fcimb.2020.00107.
Aljindan, R. Y. & Alkharsah, K. R. (2020) Pattern of increased antimicrobial resistance of Salmonella isolates in the Eastern Province of KSA. Journal of Taibah University Medical Sciences. 15 (1), 48-53. Available from: http://dx.doi.org/10.1016/j.jtumed.2019.12.004. Available from: doi: 10.1016/j.jtumed.2019.12.004.
Alt, S., Mitchenall, L. A., Maxwell, A. & Heide, L. (2011) Inhibition of DNA gyrase and DNA topoisomerase IV of Staphylococcus aureus and Escherichia coli by aminocoumarin antibiotics. Journal of Antimicrobial Chemotherapy. 66 (9), 2061-2069. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21693461. Available from: doi: 10.1093/jac/dkr247.
Clardy, J., Fischbach, M. A. & Currie, C. R. (2009) The natural history of antibiotics. Current Biology. 19 (11), R437-R441. Available from: https://search.datacite.org/works/10.1016/j.cub.2009.04.001. Available from: doi: 10.1016/j.cub.2009.04.001.
Conly, J. & Johnston, B. (2005) Where are all the new antibiotics? The new antibiotic paradox. The Canadian Journal of Infectious Diseases & Medical Microbiology. 16 (3), 159-160. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18159536. Available from: doi: 10.1155/2005/892058.
Sahana, K. S., Prabhu, A. S. & Saldanha, P. R. (2017) Usage of Cartridge Based Nucleic Acid Amplification Test (CB-NAAT/GeneXpert) test as diagnostic modality for pediatric tuberculosis; case series from Mangalore, South India. Journal of Clinical Tuberculosis and Other Mycobacterial Diseases. 11 7-9. Available from: https://www.clinicalkey.es/playcontent/1-s2.0-S2405579417300347. Available from: doi: 10.1016/j.jctube.2017.12.002.