Introduction
Ever since antibiotic resistance, doctors have been looking for ways to treat bacterial disease without creating superbugs, strains resistant to all antibiotics, broad-spectrum and narrow-spectrum, that would kill it.
Superbugs
Superbugs, once in a person’s body, would be nearly impossible to kill, and would easily overpower any natural defenses, resulting in hospitalization and likely death. In fact, scientists have predicted that by 2050, superbugs could kill more people than cancer.
How did we get here?
While many associate the start of antibiotics in 1928 with Alexander Fleming’s accidental discovery of penicillin, it actually started 18 years earlier when Paul Erlich developed salvarsan. Penicillin is a broad-spectrum antibiotic, also known as a β-lactamase antibiotic. Penicillin was a fungus, discovered on a petri dish. It took 17 years of trials of stability and purification, Fleming himself abandoning the venture after 12, but eventually penicillin reached shelves in 1945. Penicillin was touted as a cure-all, and so it quickly became used to treat everything from strep throat to the common cold. Many people treated themselves because antibiotics did not require a doctor’s prescription, resulting in people incorrectly dosing themselves and developing resistance. While penicillin resistance was discovered in 1940, the first case observed in people was in 1947. Many other antibiotics have been used, and resistance has been developed over and over again. Through the end of the 1900s, antibiotic resistance grew and grew until it developed into a fully-fledged crisis in the early 2000s.
What is an antibiotic?
An antibiotic is an agent, natural or synthetic, whose main goal is to kill bacteria. Antibiotics originate from fungi, actinomycetes (a kind of gram-positive bacteria), other bacteria, or synthetic. Antibiotics not only destroy harmful bacteria but also healthy gut microbiota, which could lead to a whole host of problems, primarily a Clostridium difficile infection. Common antibiotics include β-lactams, aminoglycosides, chloramphenicols, tetracyclines, and carbapenems.
How does resistance develop?
Resistance spreads between bacteria through conjugation, a type of horizontal gene transfer. Bacteria all contain plasmids, a self-replicating circle of DNA. These plasmids can contain any gene that the bacteria select to conjugate. When one bacteria develops resistance, it puts that gene in its plasmid, and then shares that gene to other bacteria through their pili (short, hair-like structures), spreading resistance. Bacteria also undergo binary fission, so resistant bacteria will survive longer to reproduce than bacteria without resistance, thus selecting a resistant population.
MRSA
Methicillin-resistant Staphylococcus aureus is a bacterium that caused large problems in the early 2000s due to its multidrug-resistant (MDR) capabilities. MRSA causes skin infections but could lead to pneumonia and sepsis. Its ability to be transmitted by skin-to-skin contact makes it especially dangerous. In recent years, MRSA has caused more deaths than HIV/AIDS and tuberculosis combined (Lin et al., 2017).
What are bacteriophages?
Bacteriophages are viruses that only infect and replicate inside bacteria. Phages cannot replicate by themselves; they require a host. They act similarly to narrow-spectrum antibiotics, targeting only a few species, maybe even one genus, of bacteria. This narrow range is due to phages only being able to infect bacteria that have their complementary receptor. There are two different types: lytic and lysogenic. Lytic phages cause the cell to lyse and are effective in combating AMR since they do not provide bacteria with an opportunity to develop resistance. However, lysogenic phages store their DNA in the bacterial genome, which does little to combat infection and could potentially contribute to the spread of AMR. There are over 1031 phages in the world at any given time, and they are responsible for the deaths of 20-40% of marine surface bacteria (Lin et al., 2017).
Resistance
Bacteria can develop resistance to phages as well as antibiotics, which may involve adding phage DNA into the CRISPR/Cas9 system. However, phages can evolve at the same rate as bacteria, something that antibiotics aren’t capable of. Bacteria and phages exist in a constant “arms race” of sorts, constantly evolving to overwhelm the other side.
What is phage therapy?
Phage therapy is a suggested treatment that uses phages to kill bacteria and skip antibiotics altogether, thus preventing a continuation of antibiotic resistance. Early trials of phage therapy proved ineffective, although current scientists attribute this to a lack of understanding. Phage therapy was introduced in 1919 by French scientist Felix d’Herelle.
Phage therapy trials now have reduced mortality significantly in both animals and humans. Recent studies testing the effects of phage therapy on Pseudomonas aeruginosa-affected mice found that phage therapy reduced the mortality rate by 66.7% compared to 0% in the control group (Watanabe et al., 2007). Several similar studies have been conducted, for example, where 11 out of a group of 12 mice were affected with C. difficile when treated with bacteriophages. However, all 12 mice treated with clindamycin passed away.
Bibliography
Image Credit: Kurzgesagt. (2018, May 13). The Deadliest Being on Planet Earth – The Bacteriophage. YouTube. https://www.youtube.com/watch?app=desktop&v=YI3tsmFsrOg.
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