8 controversies about phage therapy

Phage viruses have attracted a great attention  recently as it is now considered one of the best alternatives to antibiotics.
Phages are the viruses that can replicate in the bacterial host cells, kill pathogenic bacterial cells, and are able to produce new lytic phages to keep pace with the mutation of pathogens. However, the replacement of antibiotics by phages in the treatment of bacterial diseases encounters several controversies because of the following reasons:

(1) Since phages are limited to specific bacterial host, it can’t kill a wide range of pathogenic bacteria. Therefore, the specific bacteria causing infection needs to be determined with accurate diagnosis before using phage therapy.

(2) Since phages are viruses, the immune system may rapidly eliminate them from the systemic circulation before viruses reach in the target sites, or, the adaptive immune defense mechanisms may inactivate them resulting in the failure of treatment.

(3) Bacteriophages are able to transfer their own DNA from one bacterial cell to another. This causes the transfer of pathogenicity determinants and virulence factors, resulting in the development of a new microbe or even more resistant bacteria.

In some cases, phage from lytic cycle can enter the lysogenic cycle causing it possible to integrate their phage DNA into bacterial chromosome or to pass their phage virulence factors to the host bacteria.

(4) Pharmacokinetic properties of phages are not known exactly. Therefore, the optimal dose, route of administration, frequency, and duration of treatment still need to be defined accurately before widespread clinical trials are taken.

(5) Phage therapy is dependent on time-settings. So the use of phages at the early stage of disease could give a better therapeutic effect. For example, when the phages were used immediately after the infection of E. coli, the result was 100% effective; whereas when phage treatment was carried out 16 h after infection, the therapy wasn’t so effective.
(6) Phages, upon killing Gram-negative bacteria, can cause it to release of toxins, e.g., endotoxin (LPS), in large amounts. This may cause several side effects on the host such as fever.
(7) Bacteria may acquire resistance to phages by mutation. The rate mutation in antibiotics and phages are 10−7 and 10−6, respectively. The bacteria become resistant to a specific phage by several mechanisms. Loss or lack of receptor, structural modification, and/or masking of the receptor may avoid the phage from binding to the bacteria and prevent further growth of phages particle.

The bacteria may also become resistant to a phage through several other methods such as the prevention of phage DNA integration into bacterial chromosome by superinfection exclusion system (Sie), the destruction of phage DNA by restriction-modification defense system or by clustered regularly interspaced short palindromic repeats (CRISPR), and the inhibition of phage replication, transcription, translation, or virion assembly by abortive infection system.

(8) Bacteriophages have the ability to survive in the intestines when bacterial counts reach certain numbers. Phages can only reduce the number but not completely eradicate the whole population of S. typhimurium in the animal intestines.


See more:

10 Reasons of antibiotic resistance in Bacteria

10 phages used onto food to prevent bacterial pathogens

10 phages that cause human disease

10 advantages of using phage therapy over antibiotics

Five limitations of phage therapy

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