Microcins: Unlocking A New Defense Against Cholera Infection

Written by: Amanda Benneh

Edited by: Ellie Sung

Illustrated by: Alicia Chang

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Introduction

Limited access to safe water, basic sanitation facilities, and poor hygiene practices have fueled the continued spread of severe bacterial disease in regions such as Sub-Saharan Africa and Southeast Asia. These infections, transmitted through the ingestion of contaminated water and food, pose a serious global health threat, disproportionately affecting underserved populations with high transmissibility [26]. Warm climates, frequent flooding, and inadequate sanitation efforts increase the risk of contamination of drinking water with bacteria, making areas like Sub-Saharan Africa and Southeast Asia highly susceptible to infection outbreaks [1]. Cholera, a bacterial infection of the small intestine caused by the bacterium Vibrio cholerae, causes an estimated 1.3 to 4.0 million cases and 21,000 to 143,000 deaths according to the World Health Organization (WHO) [1]. While there are current first-line treatments to manage cholera infections and alleviate symptoms, the disease’s rapid progression requires prompt attention from medical experts. Researchers have recently discovered microcins, which are small proteins secreted by bacteria that can kill Vibrio cholerae, thus lowering transmittance rates of the disease [2]. By studying the biological mechanisms of microcins and utilizing their antibacterial activity, researchers are working towards creating an effective treatment to clear infections and eliminate the devastating spread of cholera.

Cholera

Cholera is an acute diarrheal infection caused by the consumption of food and water contaminated by the bacterium Vibrio cholerae (V. Cholerae) [1]. V. cholerae naturally reside in saltwater containing human and animal waste, and can be present in trace amounts in undercooked seafood and unsanitized drinking water [3]. After food and water is contaminated with bacteria, V. cholerae produces a toxin in the body called choleragen, a bacterial toxin that interferes with ion transport in the intestines [3]. This causes the small intestine to release large amounts of water, leading to severe dehydration and an imbalance of electrolytes [3]. Though most infections with V. cholerae are asymptomatic, bacteria can survive and spread through feces for up to 1–10 days, causing rapid transmission in communities without proper water quality monitoring, access to diagnostic tools, or hygiene practices to prevent bacteria spread [1]. The most common symptoms, appearing anywhere from 12 hours to 5 days after exposure, include diarrhea, nausea and vomiting, dehydration, muscle cramps, and shock [4]. Among the most affected countries, the highest number of cases reported come from South Sudan, Afghanistan, Yemen, the Democratic Republic of the Congo, and Angola [5]. Current treatments, including antibiotics and vaccines, can reduce the rapid onset of symptoms associated with dehydration for the majority of cases within these countries. The current first-line treatment, Oral Rehydration Therapy (ORS), uses fluids containing electrolytes and carbohydrates that help increase absorption of sodium and fluid in the small intestine [6]. ORS treats dehydration in patients suffering from diarrheal symptoms from cholera, and allows for proper body function. Alongside ORS, antibiotics can be used to shorten the duration of infection; however, antibiotic resistance remains a barrier to their efficacy over time [6]. As a result of these limitations, scientists have started to shift their focus towards the possibility of a new approach for killing V. cholerae [2].

Discovery of Microcins

Microcins are small proteins secreted by bacteria found in the gut that kill harmful bacteria. In the 1980s, scientists discovered microcins due to their presence in Escherichia coli (E. coli) [2]. They observed the defense systems of E. coli against other bacteria and concluded that microcins contributed to E. coli’s antibacterial mechanisms by targeting and inhibiting the growth of other bacterial cells [7]. While killing unwanted bacteria, they also help keep a healthy balance of good microbes in the body, which supports essential functions like digestion and metabolism [7]. Most importantly, harmful bacteria are not resistant to microcins, contrasting with bacteria’s resistance to other existing antibiotic treatments [2]. Therefore, scientists are working towards a deeper understanding of the structure and location of the genes coding for microcins in bacterial cells to harness microcins' natural antibiotic properties. By identifying and utilizing healthy bacteria that successfully produce microcins in the human gut, scientists can effectively kill infectious bacteria in patients.

Current Research

To study the use of microcins for antibacterial treatment, scientists must understand how bacteria produce microcins. To do this, researchers located and identified the genetic sequence that codes for microcins in bacterial DNA. However, these sequences are short and difficult to isolate [7]. To identify the amino acid sequence, the building block of proteins that make up microcins, scientists targeted a larger protein called the peptidase domain-containing ABC transporter (PCAT) in bacterial DNA [2]. PCAT is often found next to microcins and is responsible for transporting microcins out of the bacterial cell to the gut to begin eliminating other bacteria [2]. By using PCAT to locate neighboring microcin sequences, scientists discovered a group of microcins from V. cholerae samples. Specifically, one microcin, MvcC, showed antibacterial activity against bacteria that cause cholera and was able to eliminate competing microbes in the microbiome [2]. MvcC kills V. cholera bacteria by recognizing a surface protein on the outer membrane of the V. cholera cell called OmpT [2]. OmpT allows microcins to cross the membrane and enter the cell they are attacking [2]. Once in the cell, the microcin binds to another protein, OppA, which disrupts the inner membrane and damages the bacteria [2]. While the cost and complexity of developing this treatment may limit its accessibility for vulnerable populations, MvcC has been shown to effectively eliminate V. cholerae, making it a promising tool for clearing cholera infections.

Conclusion

These results highlight microcin's ability to act as a “natural antibiotic” made by microbes present in the human body to prevent the development of V. cholerae. Future directions in this research include mutating MvcC to strengthen its antibacterial ability and structure in the body, using AI technologies to discover more microcins, and identifying the most effective bacteria to produce microcins in novel antibacterial treatments [2]. The ongoing research of microcins opens possibilities for breakthrough treatments and is a promising effort to mitigate the devastating transmission of cholera.

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References

[1] World Health Organization. (2024, December 5). Cholera. World Health Organization. https://www.who.int/news-room/fact-sheets/detail/cholera

[2] Kim, S.-Y., Randall, J. R., Gu, R., Nguyen, Q. D., & Davies, B. W. (2024). Antibacterial action, proteolytic immunity, and in vivo activity of a Vibrio cholerae microcin. Cell Host & Microbe, 32(11), 1959–1971.e6. https://doi.org/10.1016/j.chom.2024.08.012

[3] Ojeda Rodriguez, J. A., Hashmi, M. F., & Kahwaji, C. I. (2024, May 1). Vibrio cholerae infection. In StatPearls [Internet]. StatPearls Publishing. Available from https://www.ncbi.nlm.nih.gov/books/NBK526099/

[4] Centers for Disease Control and Prevention. (2024, May 12). Cholera. U.S. Department of Health and Human Services. https://www.cdc.gov/cholera

[5] European Centre for Disease Prevention and Control. (2025, March 24). Cholera worldwide overview. European Centre for Disease Prevention and Control. https://www.ecdc.europa.eu/en/cholera-worldwide-overview

[6] Murphy, C., Hahn, S. S., & Volmink, J. J. (2002, July 22). Reduced osmolarity oral rehydration solution for treating cholera. Cochrane Database of Systematic Reviews, 2002(3), CD003754. https://doi.org/10.1002/14651858.CD003754

[7] Airhart, M. (2024, September 11). Newly discovered antimicrobial could prevent or treat cholera. The University of Texas at Austin. https://news.utexas.edu/2024/09/11/newly-discovered-antimicrobial-could-prevent-or-treat-cholera/