Phage Therapy for Drug-Resistant Pathogens
Section
By Katie Orefice
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In this project, I will be researching phage therapy as a defense against drug-resistant pathogens, specifically bacteria. Typically, antibiotics are used in order to combat bacterial infections and have had a lot of success. Although, when antibiotics are used often, bacteria is capable of developing a resistance to the drug, rendering it much less effective. A newer potential defense of pathogens is phage therapy. Phage therapy uses bacteriophages, which are viruses that target and infect bacteria. Each type of bacteria is susceptible to a number of bacteriophages [1]. When using a bacteriophage to target a pathogen, bacterial lysis often occurs, leading to the breakdown of a cell’s membrane and bursting of the cell [1]. This would be a successful result in targeting a pathogen. The use of phage therapy actually dates back to the early 1900s, even before antibiotics were discovered. Once antibiotics were widely used, phage therapy dissipated but now that bacteria are developing drug-resistant characteristics, the use of phage therapy has gained a renewed interest and is continuously expanding.
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Bacteriophage Function
Bacteriophages are known as viruses that specifically infect bacteria. In terms of human health, bacteriophages are present in the intestinal community, which help with digestion, immune system function, and mental health [textbook chapter 6].
In order for bacteriophages to function in combating bacteria, they must begin an infection cycle. To start, they attach to the surface of a host cell, which is allowed by certain proteins on the host cell surface, called cell-surface receptors [chp 6]. This protein described actually performs a very important function for the host cell, but the bacteriophage has evolved to use it to its advantage, such as attachment. Once attached, the phage injects its genome into the cell through the cell envelope. Once the phage’s DNA is inside the cell, replication in a lytic cycle begins. As many progeny phages are assembled as possible in this lytic cycle [chp 6]. Not only are the phage genomes replicated, but the corresponding enzymes and proteins are also assembled. Once enough progeny phages are created, the host cell lyses, meaning that the cell wall bursts which releases the progeny [chp. 6]. The phage then inserts its DNA into the host cell’s cytoplasm, leading to the expression of phage genes by the host cell RNA polymerase and ribosomes [chp. 6]. Phage genomes are continuously replicated, along with enzymes and ribosomes that then produce the phage capsid proteins. Lastly, the phage genome expresses an enzyme that lyses the host cell wall, which releases these completed virus particles [chp. 6]. With the destruction of the host cell wall, this leads to the destruction of the cell, and therefore the bacteria, making it clear that bacteriophages can be instrumental in the killing of bacteria.
Section 2
How do pathogens become drug resistant?
Antibiotics have been widely used to combat bacterial infections, although it is well known that bacteria are capable of developing resistance to certain antibiotic medications. This is a major threat to global health due to the increasing antibiotic resistance levels due to antibiotic overuse. There are various mechanisms that lead to antibiotic resistance in pathogens, such as drug target modification, molecular bypass, active efflux, and the chemical modification of the compound [mechanisms of resistance]. In drug target modification, it is possible that a point mutation occurs in specific genes, which can change the amino acid that is present, leading to an alteration in protein structure, preventing the binding of antibiotics and therefore antibiotic function [2]. In molecular bypass, microbes can avoid antibiotic action through specific avoidance mechanisms. For example, in vancomycin resistance, the substitution of an amide bond of D-Ala-D-Ala with an ester linkage gets rid of a hydrogen bond donor, causing electronic repulsion which therefore prevents binding of the antibiotic, one example of avoiding antibiotic function without mutations [2]. There is also active efflux, which is essentially the removal of antibiotics from the cell. Proteins are in charge of this removal, along with proton pumps [2]. Lastly, in chemical modification, enzymes catalyze the inactivation of specific antibiotics [2]. Through the various, complex mechanisms of antibiotic resistance, it is clear that other manners of pathogen defense will be necessary to combat these antibiotic-resistance bacteria.
Why would phage therapy be useful? One possibility when exploring alternatives to antibiotics in bacterial defense is phage (bacteriophage) therapy. Phage therapy was actually first described in 1907 by Félix d’Herelle in France, even before antibiotics were discovered [chapter 5]. It was explained that every type of bacteria is susceptible to a certain limited number of specific types of phages [3]. Due to the fact that when bacteria are infected by bacteriophages, it often leads to lysis, this technique was considered feasible for the treatment of bacterial infections, as long as the phage specific was to the pathogen [3]. There was some success and some failure when the experimentation began, as phages were used to treat various illnesses such as cholera or typhoid fever, by giving a patient phage in an open wound, or orally provided through aerosol or injection [3]. As soon as antibiotics were discovered and had success, phage therapy was placed aside, but it has become much more relevant today with the increase in antibiotic resistance.
Section 3
Include some current research, with at least one figure showing data.
Section 4
Conclusion
Phage therapy demonstrates massive potential, not only in the medical field but in aspects of agriculture, ecology, and overall public health. Research on the applications of phage therapy is continuing and further depicts possibilities in terms of the expansion of antibiotic resistance. In terms of the medical field, antibiotics have been very successful in the treatment of bacterial infections, but as bacterial resistance is on the rise, so are alternatives of combating these pathogenic infections. Whether through the use of the combination of phage cocktails with antibiotics or genetically modified phages, bacteriophages offer many possibilities for the future of medicine and in combating pathogenic infections.
References
Authored for BIOL 238 Microbiology, taught by Joan Slonczewski, 2021, Kenyon College.
