Written by Jai Singh ‘26
Edited by David Han ‘24
Superbug vs. Antibiotic [1]
Introduction
After its discovery in 1928 by Alexander Fleming, Penicillin became the weapon of choice against several respiratory tract infections [2]. It was the first in a new class of drugs called antibiotics – a novel form of defense developed to tackle the constant onslaught of evolving bacterial infections.
Antibiotics work by targeting and disrupting many critical aspects of a cell, from the cell wall to reproduction to protein synthesis. After they became generally available in the 1940s, life expectancy increased, people survived deadly infections more often, and surgeries became safer [3]. Unfortunately, in 1947, only four years after the start of mass-produced Penicillin, the first resistant bacterium was discovered. Today, 700,000 people die every year from bacterial infections resistant to antibiotics [4].
Antibiotic resistance develops when bacteria fight back against the mechanisms antibiotics employ to kill or stop their growth. They either do this by identifying the antibiotic’s active compound and ejecting it from the cell before it can cause damage or by evolving adaptations to overcome the antibiotic’s attack. Resistance can be acquired through three possible methods of gene transfer: mutation, plasmid exchange, and obtaining genetic information from dead bacteria [5]. Here, we will specifically examine plasmid exchange, which falls under the greater umbrella of horizontal gene transfer, an intra-generational method by which genetic information can be transferred. This means that once one bacterium develops antibiotic resistance, it can quickly spread to other bacteria. This article begins by examining the process of plasmids exchange, followed by the effects of this transfer, and concludes with thoughts regarding the resultant phenomenon of superbugs.
Plasmids
The term plasmid was first introduced in 1952 by Joshua Lederger as a generic term for any ‘extrachromosomal hereditary determinant’. ‘Extrachromosomal’ refers to DNA outside of the typical chromosome [6]. Plasmids are separate circular DNA sequences that, unlike chromosomes, can be transferred between bacteria. The vagueness of this definition is necessary; plasmids can do any number of things, from killing bacteria of a closely related strain to breaking down unfamiliar compounds to even turning a host bacteria into a pathogen [7].
Figure 1. The E. coli DM0133 plasmid annotated for the genes with a known function [8]
Figure 1 is a plasmid, specifically plasmid 0133. It has 94585 base pairs and codes for, among other things, tetracycline resistance. Tetracycline is a protein synthesis inhibitor - it kills cells by blocking the attachment of tRNA to the ribosome. Plasmids fall under the general umbrella of MGEs, or Mobile Genetic Elements. MGEs refer to genetic material that can transfer between different organisms. As such, the trait coding for tetracycline resistance can be transferred to other bacteria.
Horizontal Gene Transfer
Horizontal gene transfer (HGT), a primary mechanism driving antibiotic resistance in bacteria, is an intragenerational method of genetic transfer that involves bacterial plasmids. For a gene to be horizontally transferred, at four steps need to occur. Step one involves a nucleic acid such as DNA or RNA being prepared for transfer, often through plasmid replication. After this is the transfer step, which usually involves physical contact between the donor and recipient organism through a structure called a pilus. The next step is when the nucleic acid enters the recipient organism. After the genetic material enters the recipient, the nucleic acid molecule being established in the recipient as either a self-replicating element or being recombined with or transposed into the recipient’s chromosome. An example of HGT can be seen in Figure 2, which illustrates what is happening in steps 1 - 4 as described above.
Figure 2. Example of plasmid exchange via horizontal gene transfer [10]
Current research indicates that horizontal gene transfer is a significant driving factor of antibiotic resistance. A study by Schuurmans et al examined the relationship between selection pressure and antibiotic resistance by measuring the rate of successful plasmid transfer in response to different levels of selection pressure. It found that moderate selection pressures select most effectively for transconjugants. In other words, exposure to sublethal levels of antibiotics is the primary factor driving the proliferation of resistance [11]. The processed data from this experiment can be seen below in Figure 3. It provides a valuable understanding of the mechanism which controls how well or frequently plasmids transfer between bacteria. Additionally, the information from this study can give us insight into implications for how to optimize antibiotic use in a clinical setting.
Figure 3. Processed data from a study investigating how different antibiotic concentrations affect the frequency of transfer and establishment of antibiotic resistance plasmids [8].
Superbugs and Concluding thoughts on Antibiotic Resistance
'Superbugs’ refers to a phenomenon in which bacteria evolve to become highly resistant to the antibiotics used to treat bacterial infections. Because of increasing concern around superbugs, the WHO has warned of a ‘Post-Antibiotic Era,’ where the simplest of infections may be untreatable [4]. The overuse of antibiotics is the most important factor contributing to this problem [11]. There are multiple steps that can be taken to address what is fast becoming a critical issue for humanity as a whole.
From a global perspective, governments worldwide could develop and enforce meaningful restrictions on the use of antibiotics on livestock. This, in turn, might help limit the rise of superbugs and their potential transfer to humans through dairy and meat.
At the national level, antibiotic use should be strictly regulated. These drugs should be used carefully and sparingly to treat active infections instead of being doled out prophylactically. To aid the effort, pharmacies could also increase the scrutiny of prescription antibiotics, ensuring use only where truly necessary rather than (as often happens now) for common colds and seasonal flu. Patient education should be prioritized through public health information campaigns to ensure those taking antibiotics understand the importance of completing their regimens. Storing and self-prescription should be discouraged [12]. Accountability measures could be implemented for check-ins and follow-ups to support these initiatives at convenient touchpoints, including pharmacies and primary care physician offices.
Reduced usage of over-the-counter antimicrobials and bactericides would also contribute to tackling the problem. Health organizations could educate the public on the adverse effects of antimicrobial hand soaps and encourage handwashing with regular soaps, which are just as effective at killing disease [13].
Regular screening of health facilities can ascertain whether biofilms and superbugs are in check and not growing in clinical areas and surgical rooms. Additionally, patients known to be infected should be quarantined to prevent them from coming into contact with bacteria that may get the resistance gene [14].
Rising levels of resistance could also be addressed by introducing new antibiotics to combat threats. An example of this is ‘Halicin,’ an antibiotic recently discovered using machine learning by MIT researchers [15]. This tactic would extend the efficacy of antibiotics. A more stable, longer-term solution could potentially be vaccines that encourage innate immunity [16].
However, all the tactics mentioned above, taken in isolation, might only prolong the inevitable resistance that would eventually arise. The key to overcoming the prevalence of antibiotic resistance most likely lies in finding ways to change behavior on a larger scale. A multi-pronged, integrated global effort might be the only way for humanity to truly tackle and overcome this existential challenge.
References
[1] Cartoon representation of a superbug [Internet] [cited 2023 Mar 8] Avaliable from: https://stock.adobe.com/images/cartoon-representation-of-a-superbug-a-microorganism-being-strong-and-tough-because-of-drug-or-antibiotic-ideal-for-informative-and-medicinal-materials/169139284
[2] Alexander Fleming discovery and development of penicillin - landmark [Internet]. American Chemical Society. American Chemical Society; [cited 2023 Mar 8] Available from: http://www.acs.org/content/acs/en/education/whatischemistry/landmarks/flemingpenicillin.html
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[8] Plasmid DM0133 and antibiotic pressures, [Internet] [cited 2023 Mar 8] Available from: pubmed.ncbi.nlm.nih.gov/24525238/.
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[11] Announcements: get smart about antibiotics week [Internet] Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 2013. [cited 2023 Mar 8] Available from: www.cdc.gov/mmwr/preview/mmwrhtml/mm6245a7.htm.
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[13] FDA says germ-killing soap could pose health risks [Internet] WMAZ, WMAZ, 2013. [cited 2023 Mar 8] Available from: www.13wmaz.com/article/news/health/fda-says-germ-killing-soap-could-pose-health-risks/93-327095296.
[14] Conan, N. Hospitals fight to stop superbugs' spread [Internet] NPR, NPR, 2012. [cited 2023 Mar 8] Available from: www.npr.org/2012/09/18/161355297/hospitals-fight-to-stop-superbugs-spread.
[15] Trafton, A. Artificial intelligence yields new antibiotic [Internet] MIT News, Massachusetts Institute of Technology, 2020. [cited 2023 Mar 8] Available from: news.mit.edu/2020/artificial-intelligence-identifies-new-antibiotic-0220.
[16] Mackenzie, D. If it stops plague, will it stop hospital superbugs?” [Internet] New Scientist 2006. [cited 2023 Mar 8] Available from: www.newscientist.com/article/mg19125703-900-if-it-stops-plague-will-it-stop-hospital-superbugs/.