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Nature’s Evolving Assassins: How Antibiotic Resistance is Threatening Our Ability to Fight Disease

AMBIKA GROVER, Harvard College '27

THURJ Volume 14 | Issue 2


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Fig. 1. The bacteria make their way toward the innermost portion of the petri dish, developing antibiotic resistance in response to antibiotic exposure. Courtesy of the Baym lab. 

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Fig. 2. Over 11 days, bacteria have reached the 1000-unit innermost part of the Petri dish due to numerous mutations that made it more resistant. Courtesy of the Baym lab. 

Combating disease remains the tireless goal of the research community, as biomedical innovations undoubtedly lead to longer, happier, and more fulfilling lives. In the clinical context, this has propelled humanity to seek solutions for many prevalent diseases. Today, a growing challenge in engineering a modern medical defense system lies in resolving a challenge of our own creation: growing resistance to the powerful antibiotics used in the treatment of infectious diseases (Muteeb et al., 2023). Our attempts to ensure health have thus revealed themselves as double-edged swords, requiring caution and moderation.

Understanding the duality of antibiotics starts with an unusually large petri dish inside the Baym Lab, nested in Harvard Medical School’s Department of Biomedical Informatics and Microbiology. For the Baym lab, their “Mega-Plate Petri Dish” is a revealing glimpse into the capacity of antibiotic resistance. This experiment begins with a 2-foot by 4-foot petri dish divided into nine segments and covered in thick agar (a cooled gel-like substance that provides nutrients for bacteria). Different amounts of antibiotics are added to the gel, starting from the corners of the dish. At the furthest corners, there is 0 antibiotic concentration. With each n integer step from the corners, the researchers add 10^n units of antibiotic. If introduced immediately, there is no chance of bacteria survival at the innermost layer, which consists of 1000 units of antibiotics. 
The setup of the Baym lab’s mega-plate Pietri dish remains incomplete. Now loaded with antibiotics, the bacteria is introduced: the researchers prepare Escherichia coli, more commonly known as E. coli. (often recognized for its role in foodborne diseases). A variety of antibiotic and bacterial candidates could be substituted for this experiment. These include penicillin, commonly used to treat Streptococcal pharyngitis (the bacteria that causes strep throat); ampicillin, a medication used to treat meningitis (inflammation of the brain and spinal cord membranes); and tetracycline, a broad-spectrum antibiotic intended to treat infections affecting the skin (NHS, 2024). 

E. coli spreads quickly to the portion of the plate with no antibiotic, as expected. It additionally survives the layer consisting of one antibiotic dose. To survive, E. coli is required to adapt, resorting to its natural adaptation mechanisms. As the bacteria travels inwards, mutants gradually appear as white clusters; these mutant bacteria resist the antibiotic. After a slight pause when the bacteria reach 10-unit barrier, another new mutant is formed (Fig. 1). Over 11 days, bacteria crawl to the 1000-unit innermost part of the Petri dish, surviving in an environment where they would have died just days previously (Fig. 2). 

What are the implications of the evolving mutations of E. coli and other bacteria in the real world? In clinical settings, bacteria can evolve quickly and threaten already immunocompromised patients with little warning. Antiboitic resistance erodes physicians’ ability to combat infectious diseases including tuberculosis, tetanus, cholera, and UTIs, among many others. This resistance also impacts the health of animals and plants, thereby diminishing productivity and endangering food security. Most importantly, the development of resistant bacteria is a direct conscience our reliance on antibiotics to defend against disease (WHO, 2022). 


An Overview of Antimicrobial and Antibacterial Resistance 

The broader category of antimicrobial resistant (AMR) microbes–occuring when viruses, bacteria, and other organisms evolve mechanisms to protect themselves from human therapies–result in the deaths of least 1.27 million people annually. Moreover, the specialized antibiotics used to treat already multidrug-resistant microbes costs the United States alone $4.6 billion every year (CDC, 2021). These challenges are relatively normal: AMR was first observed in the 1940s and 1950s in the form antibiotic resistance–AMR applied to specifically to bacteria . The first hint of the danger of antibiotic resistance came in Alexander Fleming’s 1945 Nobel Prize acceptance speech, in which he suggested that it “would not be difficult” to make microbes resistant to penicillin in the laboratory (ReAct, 2020). These observed effects quickly escalated. For example, Staphylococcus aureus, the cause of staph infections, is a bacteria that affects the skin and spreads through contact. Identified as resistant to penicillin by Mary Barber in Britain in the early 1960s, S. aureus rapidly spread worldwide, undeterred by antibiotics intended to treat it (Podolsky, 2018).

Bacteria use two primary mechanisms to withstand the effects of antibiotics (Habboush, 2023). Often, bacteria can acquire resistance via a new genetic mutation that helps them survive when exposed to antibiotics. Alternatively, bacteria may obtain DNA from another already resistant bacterium via multiple potential mechanisms. The former is known as intrinsic resistance; for example, an antibiotic designed to target the wall of a bacterium cannot do so if a strain of S. aureus lacks a cell wall due to mutation. This is an example of an advantageous mutation likely to be passed down from generation to generation through vertical mutation (Fig. 3). The second mechanism—horizontal gene transfer—happens through transformation, transduction, or conjugation (Fig. 3). In transformation, a bacterium engulfs a piece of ambient DNA. In transduction, DNA is transferred from one bacterium to another via a virus. In conjugation, DNA passes through an intercellular tube-like structure (Cecchetelli, 2019). Together, these evolutionary systems can defeat our ability to fight and cure disease. Resistant E. coli. and S. aureus remains a concern in nearly 80 countries, where 42% and 35% of strains resist the best available antibiotics to treat them.

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Fig. 3. An overview of vertical (passing down mutations) and horizontal evolution (conjugation, transduction, and transformation) in bacteria, which help to make them more resistant (FutureLearn, n.d.). 

Molecular Mechanisms of Antibiotic Resistance

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Fig. 4. An illustration of various antibiotic resistance strategies of bacteria (Winstred-Yuen et al., 2018). 

 Antibiotics can be either synthetic or naturally derived therapeutics; they often interact with bacterial receptors to gain entry into the cell, provoking specific cell responses and mechanisms of resistance in the organisms they target. In addition to their role in treating infectious diseases, advancements in antibiotic development have propelled breakthroughs in the context of cardiovascular disease, in immunosuppression (helpful in bone marrow or organ transplant contexts), and in cancer treatment.

    As discussed, bacteria can develop unique traits that enable their survival despite exposure to antibiotics. For example, chemotaxis is the process of directed cell mobility that enables bacterial “swimming” in response to a given stimulus (ScienceDirect, n.d.). The pathogen Pseudomonas aeruginosa (primarily associated with pneumonia) exhibits chemotaxis in a surprising manner; counterintuitively, these bacteria swim toward antibiotics. In doing so, the bacteria move as if they are responding to a competing bacterial colony and are preparing to become suicidal, releasing molecules to defend against the competing colony in the process. In reality, they are lured to their deaths by antibiotics. This self-induced destruction explains just one situation in which clinical antibiotics help eliminate pathogens (Oliveira, et al). 

    With this framing in mind—the high levels of fluidity that bacteria possess and their ability to rapidly adapt—how do bacteria develop an affinity for resistance? Two primary mechanisms of antibiotic resistance are (1) the creation of efflux pumps that can push antibiotics out of the bacteria and (2) the use of deactivating enzymes (known as transferases) that prevent adequate binding of the antibiotic to its intended target (Fig. 4). First, efflux pumps serve as transporters that remove harmful substances from the internal environment of bacteria to the outside. This is important given that most antibiotics that interact with a specific target accumulate within bacterial cells. Efflux pumps are located at the membrane of bacterial cells. When a bacteria develops a pump that recognizes the characteristic profiles of an antibiotic (through mechanisms of vertical and horizontal transfer), it becomes substantially easier for these bacteria to resist antibiotic-induced death. Notably, these efflux pumps do more than assist bacteria in antibiotic resistance: the E. coli AcrAB efflux system, for example, pumps out bile acids and fatty acids to lower bacterial toxicity (Okusu et al., 1996). Second, transferases within bacteria seek to modify the antibiotic, attempting to bind and modify it, eliminating its functionality. Often, transferase enzymes chemically substitute a functional group situated at the exterior-most position of the antibiotic, preventing binding (Das et al., 2017). These enzymes, known as antibiotic-modifying enzymes, are the largest group of enzymes that play a direct role in antibiotic resistance. 

Implications of Antibiotic Resistance

 After all other antibiotics have tried and failed, treatment of bacterial infections in a clinical setting can require a drug of last resort (DoLR), which is utilized after all other drug options have been exhausted. The antibiotics falling under this classification are broadband, attempting to eliminate harmful bacteria through any means necessary. Unfortunately, due to historical usage, there is already a very high level of resistance to many last-resort antibiotics, limiting their effectivity. As such, DoLR’s are primarily regarded as a patient’s last chance when they suffer a multi-drug resistant infection (Li, et al, 2022). 
There is much to consider with respect to how to approach fighting antibiotic resistance. At Harvard and affiliate institutions, labs such as the Baym and Kahne labs are engaged on this front. However, these labs face a significant, growing challenge. There are 2.8 million infections per year in the United States attributed to antibiotic resistance. The aftermath of COVID slowed our ability to fight AMR. In the first year of the pandemic, more than 29,400 people died from AMR infections; 40% were infected at the hospital. Furthermore, funding for research investigating antimicrobial-resistant infections has decreased by 18% in recent years (CDC, 2024). 

There are also underlying social concerns associated with how bacterial infections are treated. There remains a widespread crisis of antibiotic use abuse. As Abhijit Banerjee outlines in his book Poor Economics, part of this crisis stems from the fact that many individuals with a lack of medical knowledge feel more “comfortable” being handed a pill–such as an antibiotic–to remedy their illnesses as opposed to leaving the doctor’s office empty-handed. Additionally, some individuals refuse treatment altogether, while others take over-the-counter general antibiotics without considering whether their social costs are worth the individual benefits. 

Given this diversity of behavior and belief in using antimicrobial drugs, significant work needs to be done to motivate a careful balance between antibiotic use and appropriate caution. Science must play a dual role: helping to inform the public about the necessity of treatment while ensuring this care is handled with proper diligence and caution. Without action, antibiotic resistance may quickly become one of the largest challenges of the 21st century, and the solution to this pressing issue remains as much of a question of biomedical research as of public health. Thus, only the evaluation of antimicrobial resistance at the intersection of these fields has the potential to sustain the innovations necessary  to treat infectious diseases for decades to come. 


Antibiotics. NHS inform. (2024, February 29). 

Bhaskar, Das. Antimicrobials: Meeting the challenges of antibiotic resistance through nanotechnology. Nanostructures for Antimicrobial Therapy.

Baym, M., Lieberman, T. D., Kelsic, E. D., Chait, R., Gross, R., Yelin, I., & Kishony, R. (2016). Spatiotemporal microbial evolution on antibiotic landscapes. Science, 353(6304), 1147–1151. 

Cecchetelli, A. (n.d.). Plasmids 101: Transformation, transduction, bacterial conjugation, and transfection. Addgene blog.

Centers for Disease Control and Prevention. (2021, December 13). National estimates for antibiotic resistance.

Centers for Disease Control and Prevention.

Chemotaxis. Chemotaxis - an overview | ScienceDirect Topics. (n.d.).

The discovery of antibiotics – part 1. ReAct. (2020, November 6).,occasionally%20happened%20in%20the%20body.

FutureLearn. (n.d.-a). Disease outbreaks & antimicrobial resistance. 

Habboush, Y. (2023, June 20). Antibiotic resistance. StatPearls [Internet].,Mycobacterium%20tuberculosis%20resistance%20to%20rifamycin.

Li W;Yang Z;Hu J;Wang B;Rong H;Li Z;Sun Y;Wang Y;Zhang X;Wang M;Xu H; (2022). Evaluation of culturable “last-resort” antibiotic resistant pathogens in hospital wastewater and implications on the risks of nosocomial antimicrobial resistance prevalence. Journal of hazardous materials.

Muteeb, G., Rehman, M. T., Shahwan, M., & Aatif, M. (2023). Origin of antibiotics and antibiotic resistance, and their impacts on drug development: A narrative review. Pharmaceuticals, 16(11), 1615. 

Okusu, H., Ma, D., & Nikaido, H. (1996). Acrab efflux pump plays a major role in the antibiotic resistance phenotype of escherichia coli multiple-antibiotic-resistance (mar) mutants. Journal of Bacteriology, 178(1), 306–308.

Oliveira, N. M., Wheeler, J. H. R., Deroy, C., Booth, S. C., Walsh, E. J., Durham, W. M., & Foster, K. R. (2022, December 9). Suicidal chemotaxis in bacteria. Nature News.

Podolsky, S. H. (2018, October 23). The evolving response to antibiotic resistance (1945–2018). Nature News.,and%20deaths%20worldwide%20throughout%20the

Wistrand-Yuen, E., Knopp, M., Hjort, K., Koskiniemi, S., Berg, O. G., & Andersson, D. I. (2018). Evolution of high-level resistance during low-level antibiotic exposure. Nature Communications, 9(1). 

World Health Organization. (n.d.). Antimicrobial resistance. World Health Organization.,systems%20and%20national%20economies%20overall. 
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