by Melany Su
April 2013

Hospitals, where antibiotics are widely used, are one of the most suitable places for breeding invincible bacteria.

In any population of bacteria, there can exist a few bacterial cells with genes that code for antibiotic resistance. In recent years, methicillin, an antibiotic of the penicillin family, has lost some of its effectiveness against Staphylococcus aureus, a bacterium that often causes infections of the skin, respiratory system, and digestive system. According to a study by Dr. Jason Newland, physician at the Children’s Mercy Hospitals and Clinics in Missouri, the number of children hospitalized with antibiotic-resistant staph infections increased ten times from 1999 to 2008 (Associated Press, 2010). When methicillin fails to exterminate all S. aureus bacteria in a patient, the surviving ones can exchange genes and reproduce, resulting in an entire population of methicillin-resistant S. aureus (MRSA) that can only be eliminated by a more potent drug. In the past decade, health care specialists have come across an even more alarming problem—MRSA bacteria are developing resistance to vancomycin, a powerful drug often used as a last resort (Sieradzki, Roberts, Heber, & Tomasz, 1999).

In a battle against these disease-causing agents, scientists are turning to bacteria’s natural enemy for a solution. Just as some viruses infect and cause diseases in humans, so others infect and kill bacteria. Bacteriophages, literally “bacteria eaters,” are found everywhere in nature—from murky river waters to human intestines. As the most abundant life form on earth, phages number over 1030 and destroy half of the world’s bacteria every two days (Deresinski, 2009).

A phage consists of a DNA-containing head, a syringe-like tail, and multiple tail fibers (Kursepa, Dabrowska, Switala-Jelen, & Gorski, 2009). When a phage approaches a bacterial cell’s surface, molecules on its tail fibers recognize proteins specific to that bacterium (Bradbury, 2004; Deresinksi, 2009). After attaching itself to its victim, the phage contracts its tail, injecting genetic material into the bacterium. The phage then hijacks its host, forcing it to produce new phages. At a certain time dictated by phage DNA (Wang, 2005), enzymes digest the bacterial cell wall, releasing new phages into the environment, where they attack other bacteria.

For over a century, before antibiotics were invented, scientists harnessed these “bacteria eaters” to treat diseases, a practice known as phage therapy. In 1896, British chemist Ernest Hankin discovered that water from the Ganges and Jumna Rivers could cure cholera (Parfitt, 2005; Deresinski, 2009). Frederick Twort, a microbiologist at the Brown Veterinary Hospital in London, observed a similar antibacterial phenomenon in 1915 (Bradbury, 2004; Deresinski, 2009). He grew bacterial cultures on agar plates and subjected the agar surfaces to doses of bacteriophages. Transparent spots, today known as “plaques,” appeared in these cloudy, bacteria-occupied agar plates.

Felix d’Herelle, a French-Canadian microbiologist at the Pasteur Institute in Paris, was the first to attribute these observations to bacteriophages (Summers, 2001). While stationed with French troops in 1915, d’Herelle concluded that phages promoted recovery from dysentery (Sulakvelidze, Alavidze, & Morris, Jr., 2001). After treating animal diseases with phage therapy, d’Herelle successfully attempted the technique on human beings, including four cases of bubonic plague in Alexandria, Egypt, and a cholera epidemic in Bombay, India (Deresinski, 2009; Kuchment, 2011; Summers, 2001). From then until the 1940s, phage therapy became highly popular. Commercial companies, such as the Societé Française de Teintures Inoffensives pour Cheveux (Safe Hair Dye Company of France; now L’Oréal), marketed over-the-counter phage preparations (Bradbury, 2004; Deresinski, 2009; Parfitt, 2005). In 1923, d’Herelle and Georgian bacteriologist Giorgi Eliava co-founded an institute in Tbilisi that continues to produce therapeutic phage preparations today (Sulakzelidze et al., 2001). The Eliava Institute has developed new ways of administering their products, including powder, injections, and even biodegradable artificial skin applied to wounds, called PhageBioDerm (Deresinksi, 2009; Parfitt, 2005).

Phage therapy in the West did not remain popular for long, though. Despite anecdotes of success, negative results such as toxicity, bacterial resistance, and inactivation of phage preparations by preservatives were observed (Bradbury, 2004; Foster, 2004; Parfitt, 2005). While phage therapy persisted in Germany and the Soviet Union, attention in the United States shifted to antibiotics at the advent of World War II. Longer shelf-lives, along with broad-spectrum effect, are all advantages of antibiotics over bacteriophages (Summers, 2001; Deresinski, 2009). The mixed results of phage therapy, and postwar avoidance of Soviet medicine, are additional possible reasons for which the technique was not embraced in the United States.

In response to antibiotic-resistant bacteria, however, Western countries have recently re-taken phage therapy into serious consideration. Bacteriophages offer several advantages over antibiotics. When applied to wounds, antibiotics decrease in concentration as depth into the skin increases (Bradbury, 2004). On the other hand, because phages do not diffuse through tissue as regular chemicals do, but rather “hitchhike” the cells they attack, they can not only travel deep into wounds, but also reproduce in proportion to bacterial population (Parfitt, 2005). Furthermore, although bacteria can develop resistance to both antibiotics and phages, new phage preparations can be produced within days, and clinical trials have shown that phage cocktails can circumvent resistance. A new antibiotic, in contrast, takes years to develop.

Though antibiotics are still the main weapons against bacteria in the United States, research into the potential use of phages is well under way. Vincent Fischetti, bacteriologist and immunologist at Rockefeller University, studies phage enzymes that attack anthrax bacteria (Bradbury, 2004). PhageTech, a biotech company in Montreal, Canada, uses phage proteins to identify “weak spots” on bacterial surfaces, with the goal of developing more effective antibiotics (McGill University, 2002). Numerous laboratories have characterized various phages and collected their genomes to create phage libraries for reference (Deresinski, 2009).

Nevertheless, it may be a while before bacteriophages can replace antibiotics in clinical use in the United States (Parfitt, 2005; Summers, 2001); some specialists even doubt that this will ever occur (Stone, 2002). Motivating entrepreneurs to invest in phage therapy, a century-old—and therefore not very patentable—technique is a challenge in itself (Thiel, 2004). Furthermore, acquiring FDA approval for phage cocktails appears complicated (Fischetti, Nelson, & Schuch, 2006).

Despite these financial and legislative hurdles, bacteriophages may pioneer their way into fields where regulations are less stringent, such as the agricultural sector (Stone, 2002; Thiel, 2004). Scientists, however, have gotten us closer to the potential use of phages in clinical settings. Since d’Herelle’s time, the biological nature of phages has been better researched and understood, and both scientists and companies are harnessing bacteriophages for medical purposes. Recently, wide use of antibiotics in western countries has fostered the growth of antibiotic-resistant bacteria and renewed interest in phage therapy. As investments in research and production continue to grow, phages may soon fully launch into clinics and hospitals, where they may begin to combat antibiotic-resistant bacteria.

References

Associated Press. (2010, May 17). MRSA Staph Infections in Kids Surge. CBSNews.com. Retrieved from http://www.cbsnews.com/stories/2010/05/17/health/main6490768.shtml

Bradbury, J. (2004). My Enemy’s Enemy Is My Friend. The Lancet 363, 624-625. Retrieved from http://search.proquest.com/docview/199097558?accountid=27975

Deresinski, Stan. (2009). Bacteriophage Therapy: Exploiting Smaller Fleas. Clinical Infectious Diseases 48(8),1096-1101. doi: 10.1086/597405

Fischetti, V., Nelson, D., & Schuch, R. (2006). Reinventing Phage Therapy: Are the Parts Greater Than the Sum? Nature Biotechnology 24(12), 1508-11. doi: 10.1038/nbt1206-1508

Foster, S. (2004). Bacteriophages May Foil E. coli. Medical Post 40(3), 27. Retrieved from http://search.proquest.com/docview/228805875?accountid=27975

GangaGen, Inc. Profile. http://www.gangagen.com/corporateframe.htm

Hendrix, Roger W. (2002). Bacteriophages: Evolution of the Majority. Theoretical Population Biology 61, 471-480. doi: 10.1006/tpbi.20021590

Kuchment, Anna. (2011). The Forgotten Cure: The Past and Future of Phage Therapy. New York: Springer.

Kursepa, A., Dabrowska, K., Switala-Jelen, K., & Gorski, A. (2009). Molecular Modification of T4 Bacteriophage Proteins and Its Potential Application. Folia Microbiologica 54, 5-15. doi: 10.1007/s12223-009-0002-0

Office of Technology Transfer, McGill University. (30 October 2002). PhageTech. Retrieved from http://www.mcgill.ca/files/ott/phagetech.pdf

Parfitt, G.T. (2005). Georgia: an Unlikely Stronghold for Bacteriophage Therapy. The Lancet 365, 2166-7. Retrieved from http://search.proquest.com/docview/199025825?accountid=27975

Sieradzki, K., Roberts, R., Haber, S., & Tomasz, A. (1999). The Development of Vancomycin Resistance in a Patient with Methicillin-Resistant Staphylococcus aureus Infection. New England Journal of Medicine 340, 517-523. Retrieved from http://www.nejm.org/doi/full/10.1056/nejm199902183400704

Stone, R. (2002). Stalin’s Forgotten Cure. Science 298(5594), 728-31. Retrieved from http://search.proquest.com.proxymu.wrlc.org/docview/213593809?accountid=27975

Sulakvelidze, A., Alavidze, Z., & Morris, J. G. (2001). Bacteriophage Therapy. Antimicrobial Agents and Chemotherapy, 45(3), 649–659. doi: 10.1128/AAC.45.3.649–659.2001

Summers, W.C. (2001). Bacteriophage Therapy. Annual Review of Microbiology 55, 427-451. Retrieved from http://search.proquest.com/docview/205881487?accountid=27975

Thiel, K. (2004). Old Dogma, New Tricks—21st Century Phage Therapy. Nature Biotechnology 22(1), 31-6. doi: 10.1038/nbt0104-31

Wang, I. (2006). Lysis Timing and Bacteriophage Fitness. Genetics 172(1), 17-26.doi: 10.1534/genetics.105.045922

previous article     table of contents