Bacteriophages as potential treatment option for antibiotic resistant bacteria

 

Bacteriophages as potential treatment option for antibiotic resistant bacteria

- Ritobeeti Chatterjee [sem 3 zoology]

 

An increasing number of pathogenic organisms growing resistance to the available antimicrobial drugs has caused Anti Microbial Resistance (AMR) to be classified as a rising global health concern. AMR is a classic example of random mutation and natural selection as the microorganisms grow resistance to and persist in the presence of medication meant to inhibit the growth of or kill said microorganisms. 

Antibiotic resistance is a major subfield of study under Anti Microbial Resistance (AMR), which refers to the resistance shown by bacteria to antibiotics. Antbiotic resistace has een the direct cause of 1.27 million global deaths in 2019 and has contributed to 4.95 million deaths. Resistance in bacteria might arise spontaneously due to genetic mutation, or by the process of a species acquiring antibiotic resistant strains from another.  The simplest type of resistance shown by bacteria is termed innate resistance and occurs due to a natural lack of susceptibility for the antibiotics. The resistance may be associated to the absence of a receptor for the antibiotic, low affinity for the antibiotic, cell wall impermeability, or production of enzymes which nullify the action of the antbiotic. Resistance can also be generated due to human intervention such as overuse, misuse and usage of antibiotics for treating viral infections whchleads to the generation of resistant strains in the bacteria. 

 Bacteriophage are a subclass of virus that infect bacteria.  The morphology of bacteriophages, like most viruses, comprise a core of genetic material (nucleic acid), which may be a DNA or RNA and may be double-stranded or single-stranded, surrounded by a protein coat known as the capsid. Bacteriophages can be classified into three subclasses depending on their difference in structural composition: a 20-sided head (known as an icosahedron from the Greek word eikosi meaning 20) with a tail, a 20-sided head without a tail, and a filamentous form.

The unprecedented increases in the number of bacteria growing resistance to the available antibacterial medication has urged researchers and the medical fraternity to look for plausible alternatives to the traditional approach of using antibiotics. Use of bacteriophages for purpose of treating bacterial infection, in both animals and human, has garnered much positive results over the past few years.

A strategy that has seen the maximum action and garnered the highest number of affirmative results as a plausible treatment strategy for the growing menace of Antimicrobial Resistance is phage therapy. The process involves therapeutic exploitation of bacteriophages to inhibit the growth of and extirpate selective groups of bacteria — the bacteriophages infect a proportion of the infective bacteria within the body of the host organism, either animal or human, which leads to the injection of the phage genetic material (either RNA or DNA) within the bacterial cell. The phage uses RNA polymerase of the bacteria to transcribe the phage  DNA into RNA which codes for protein. The phage DNA also undergoes replication thus leading to the formation of new phage bodies which mature within the bacterial cell. The genetic material also codes for enzymes which degrade the bacterial envelope, both cell wall and plasma membrane, holins which are a group of small proteins that degrade the bacterial cytoplasm and allow endolysin, a group of hydrolytic enzyme to degrade the bacterial cell membrane glycoproteins. This degradation causes lysis of the bacterial cell and release of the phages which go on to infect more bacterial cells. This procedure has yielded much positive results in the treatment of respiratory, wound,and chronic infections This treatment method has also proved to be efficacious in clearing persister cells, a dormant variant of normal bacterial cells which show high levels of antibiotic resistance, and bacterial biofilms.

Phages can also be used to magnify the sensitivity bacteriocidal activity of antibiotics. Unlike the former method where phages are used to kill all the desired bacterial cells, this procedure utilizes phages to target and kill selectively the antibiotic-resistant bacteria, thus leading to the reduction of total bacterial population and extermination of resistant strains and subsequent increase in effectiveness of the antibiotic medication used.

Another procedure to tackle the Antibiotic Resistance includes Phage-antibiotic synergy (PAS). This is the process in which concentration of phage bodies produced wthin the host increases in the presence of sublethal concentration of certain antibiotics. This procedure has yielded beneficial results as remedy for infections resulting from multi drug resistant bacteria, P. aeruginosa. 

Moreover, phages can be also be utilized to deliver antibiotics directly to bacterial cells, increasing the concentration of antibiotic medication at the site of infection and reducing the possible threat of side – effects, a major barrier in use of antibiotics.

Phage therapy which has shown up in the recent years as an optimistic approach to treating bacterial infections, specifically multi drug resistant bacteria, has its own set of challenges. The primary hurdle is selection of the right phage against the particular resistant strain of bacteria. Another obstacle in the field of phage therapy is the rise of  resistance to phages. Ability of the bacteria to grow resistance against phages, similar to that aganst antibiotics, is known as phage resistance. It usually occurs due to alteration of the bacterial cell envelope.  Administration of phage is a complicated procedure as they are live, self-replicating organisms; and thus the concentration of phage mixture administered to a patient may not be the exact concentration they actually receive.

Despite the difficulties highlighted above, some biotechnology firms still pursue and fund researches in the field of phage therapy on a commercial scale. BioLynceus, AmpliPhiBiosciences, Locus Biosciences, Intralytix, and Adaptive Phage Therapeutics are a few companies among others which are working to overcome the drawbacks and increase the effectiveness of phage therapy as a possible treatment option for bacterial infections.

 

References :

1. World Health Organization: WHO. (2023, November 21). Antimicrobial resistance. https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance
2. Hibstu, Z., Belew, H., Mihiretie Mengist, H., & Akelew, Y. (2022, October 6). Phage Therapy: A Different Approach to Fight Bacterial Infections. PubMed Central. Retrieved September 27, 2024, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9550173/
3. Alqahtani, A. (2023b, December). Bacteriophage treatment as an alternative therapy for multidrug-resistant bacteria. Saudi medical journal. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10712800/ 
4. Baral, B. (2023, January 24). Phages against Killer superbugs: An enticing strategy against antibiotics-resistant pathogens. Frontiers in pharmacology. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9902939/ 
5. Encyclopædia Britannica, inc. (2024, July 14). Bacteriophage. Encyclopædia Britannica. https://www.britannica.com/science/bacteriophage 
6. Nang SC;Lin YW;Petrovic Fabijan A;Chang RYK;Rao GG;Iredell J;Chan HK;Li J; (n.d.). Pharmacokinetics/pharmacodynamics of phage therapy: A major hurdle to clinical translation. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. https://pubmed.ncbi.nlm.nih.gov/36736661/ 
7. Osman, A.-H., Kotey, F. C. N., Odoom, A., Darkwah, S., Yeboah, R. K., Dayie, N. T. K. D., & Donkor, E. S. (2023, August 17). The potential of bacteriophage-antibiotic combination therapy in treating infections with multidrug-resistant bacteria. Antibiotics (Basel, Switzerland). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10451467/