Hey Steemians, in today’s article I will be talking about phage therapy (use of bacteriophage for treatment). Bacteriophage is viruses which infects bacteria and leads to their death by lytic pathway. They were first reported by Frederick Twort in 1915 and Felix d’Herelle in 1917. As we hear viruses the first which come to all of us mind is various diseases, but in this article we will be discussing about their property which is helpful to treat bacterial infection. Antibiotic resistance is global concern which researchers are facing which has eventually leaded to need of new medicines and techniques to overcome this issue. So phage therapy can be used to against antibiotic resistant bacterial strains to control their growth. One of the first time phage was used to treat many soldiers infected with bacterial diseases like dysentery and gas gangrene during World War II by Russian researchers (1).

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Before starting with mechanism by which phage therapy works let’s just first talk about biological basis of phage. Bacteriophages are bacterial parasites, to carry out biological replication bacteriophages uses bacterial machinery to replicate. Phage binds to receptors present on bacteria membrane and hijacks bacterial machinery and produces phage progeny, upon reaching certain critical mass of phage and lytic proteins leads to rupture of bacterial cell membrane and reinitiate new lytic cycle (2).

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Paul Turner group has shown that phage can be used restore antibiotic sensitivity in multidrug resistant Pseudomonas aeruginosa. The Turner group has shown that phage binds to MexAB and MexXY multidrug efflux systems of MDR P.aeruginosa (3).

The antibiotic resistant bacteria have an efflux system Mex (Multidrug efflux) which extrude antibiotics which enter into bacterial cell. It is comprised of three components: antiporter (MexB, MexY), outer membrane protein (OprM) which forms a surface exposed channel and a fusion protein which links the two proteins (4). 

The same group in 2018 has shown that phage treatment can be used in case of aortic graft with Pseudomonas aeruginosa (5).

Phage can also be used in fermentation. During fermentation process there is always risk of bacterial contamination and which result in loss. So to avoid the growth of unwanted bacterial strains specific bacteriophage can be used to kill them (6).

The advantage of using bacteriophage over antibiotic is that some antibiotics are broad spectrum which kills other bacteria also along with target but on the other hand bacteriophage are very specific they kill only specific strains and do not cause harm to other normal flora of body (7).

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Phage therapy represents a kind of biomedical “smart bomb,” affecting only a specific target and minimizing collateral damage.

Instead of using whole phage for killing bacterial cell lysin can be used for this purpose. Endolysin or lysin is a peptidoglycan hydrolase which is produced by tailed phages at the end of lytic cycle to release their progeny at the final stage of multiplication. Antibiotics such as penicillin or cephalosporin are administrated during bacterial infection as they inhibit the peptidoglycan synthesis during bacterial division but lysin attacks directly on the peptidoglycan within seconds of administration. Lysin is also effective on non-growing bacteria which remain unnoticed by antibiotic during this stage (8).

The drawback of phage mediated mechanism of bacterial cell killing is ability of bacteria to develop resistance to phage infection by changing receptors. One of the methods of overcoming phage integration into bacterial cell is by cutting nucleic acid of phage using restriction enzymes. CRISPR/Cas is also associated in overcoming phage attack by altering the receptors or complete removal of receptors. Another approach is producing of various compounds by bacterial cell which compete with cell membrane receptors for the binding site on phage (9).

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As the bacteria develops resistance to phage invasion, phages also coevolve with bacteria for example T-even type phage Ox2, recognizes OmpA of E.coli as receptor. When a mutation takes place in bacteria and OmpA is modified the phage cannot adsorb on the E.coli. But some of the phage do adsorb to bacterial cell as they coevolve with bacteria and recognize new receptor site like OmpC. It has been also shown that in the absence surface receptors like OmpA, OmpC and OmpX phages uses lipopolysaccharide as receptor (10).

Another method that can be used to forestall development of phage resistance was shown by Mzia Kutateladze and Revaz Adamia their work was published in 2003. The idea they used was to make synergistic use of antibiotic and phage to get better results. For this they used sub-lethal concentration of antibiotics, in presence of which the cell starts to compromise and by taking use of this phage accelerate lysis of infected cells and rapid spread of phages (11).   

Reference

"Stalin's Forgotten Cure". Science, 25 October 2002 v.298.

Delbruck et. al., 1940 The growth of bacteriophage and lysis the of host. 23(5),643-660.

Chan et. al., 2016 Phage selection restores antibiotic sensitivity in MDR Pseudomonas aeruginosa. Sci. Rep. (201).

Morita et. al., 2006 Antibiotic inducibility of the MexXY multidrug efflux system of Pseudomonas aeruginosa: involvement of the antibiotic-inducible PA5471 gene product. 188(5),1847-1855.

Chan et. al., 2018 Phage treatment of an aortic graft infected with Pseudomonas aeruginosa. 1,60-66.

Sturino et. al., 2006 Engineered bacteriophage-defense system in bio-processing. 4(5),395-405.

Keen et. al., 2012 Phage therapy: Concept to cure. 3,238.

Jado et. al., 2003 Phage lytic enzymes as therapy for antibiotic-resistant Streptococcus pneumoniae infection in a murine sepsis model. 52(6),967-974.

Labrie et. al., 2010 Bacteriophage resistance mechanism. 8(5),317-327.

Matsuzaki et. el., 2005 Bacteriophage therapy: a revitalized therapy against bacterial infectious diseases. 11(5),211-219.

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