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Toxin-Phage Bacteriocide as an Antibiotic Therapy


Objective:

The objective of my research is to develop an alternative method for treatment of bacterial infections using nature’s own cure: the bacteriophage. Through a variety of molecular biological techniques, bacteriophages are being enhanced to insure complete elimination of an invasive bacteria.

Why?

The natural ability of infectious bacteria to develop immunities to every antibiotic that is used against them has become an alarming health concern. It is increasingly apparent that different methods for treating bacterial infections must be developed as an alternative to antibiotic therapy.

How might one do this?

The two greatest obstacles to overcome in developing biomedical treatments are the method of delivery and the target specificity of the agent used to extinguish the bacterial infection. The delivery system must be able to withstand the body's immunity mechanisms long enough to do its job, while being specifically aimed to the targeted cell to insure that the host is left unharmed. Ideally, this type of anti-bacteria agent would be non-injurious to both the biological host and the symbiotic bacteria that normally reside in a healthy body.

Bacteriophage in Nature

Nature has provided an ideal system that fulfills all these requirements. For every type of bacteria known in nature, there is a complimentary virus, known as a bacteriophage, that specifically infects a single bacterial species.

Bacteriophage Therapy

Research using bacteriophages as therapeutic agents against bacteria dates back to the late 19th century. As early as 1898 it was found that drinking water from the Ganges River in India helped to prevent cholera epidemics from spreading. Why this worked, no one knew. By 1920 Edward Twort and Felix d’Herelle, two of the most noted pioneers in bacteriophage research, were isolating bacteriophages from several bacterial species and using them as anti-bacterial agents. But as late as 1931, JAMA concluded in a bacteriophage therapy review study, that the actual nature of the bacteriophage was unknown. What were these particles that were destroying bacteria? Were they living creatures? Or non-living anti-bacterial agents? Unfortunately, the JAMA conclusion helped stymie research using bacteriophages as anti-bacterial agents. By the early 1940’s, antibiotics were introduced to the world as a cure all for bacterial infections. Bacteriophage therapy literally came to a halt in most of the world, except for the Soviet Union and parts of eastern Europe.

The Dawning of a Revival

Today, due to infectious bacteria's increasing resistance to antibiotics, there is a revived interest in using bacteriophage therapy as an alternative to antibiotics. Though not yet perfected, bacteriophage therapy may become the treatment of choice when combating life threatening bacterial infections.

Research done in my laboratory

In nature, a bacteriophage may choose one of two pathways, or lifestyles, to propagate themselves, thus insuring their future survival. After the bacteriophage invades a susceptible host bacteria, it can choose to undergo either a lytic or lysogenic lifestyle pathway depending on environmental conditions (illustrated below). The bacteriophage that undergo a ‘lytic’ lifestyle, reproduce multiple copies of itself, then burst out of the dying bacterial cell and continue to invade more susceptible host bacteria. Alternatively, the bacteriophage may choose to undergo a ‘lysogenic’ lifestyle, integrating its own DNA into the susceptible bacterial host cell’s DNA and can remain dormant for generations. Those bacteria harboring the bacteriophage DNA continue to grow and reproduce passing the phage DNA to its offspring, unaware that they have a foreign entity secretly residing within. These lysogenic bacteria become immune to further bacteriophage infection from the same type of bacteriophage. Obviously, the decision of the bacteriophage to choose a lysogenic lifestyle can hinder phage therapy.

Currently, most phage researchers are focusing on bacteriophages that appear to undergo a lifestyle that is strictly ‘lytic ’ in nature. However, even though the bacteriophage choose a lytic lifestyle within a well defined test tube environment, this does not insure that the bacteriophage will always choose to remain lytic under normal physiological conditions found in a body. It makes sense actually, why would a bacteriophage wipe out all the susceptible bacteria that insure its ultimate survival? It is becoming apparent that seemingly lytic bacteria in a test tube may become lysogenic within the body.

This research specifically addresses the ‘lysogenic’ problem encountered in phage therapy. Bacteriophages are chosen that are specific for a certain type of bacterial infection. These bacteriophages are enhanced by introducing a bacterially recognized gene for a toxic molecule. This ‘toxic’ molecule has the unique property of being injurious ‘only’ while within a cell. Once released from the cellular environment, it becomes harmless to the cells from the outside. Using the modified bacteriophages that are carrying the gene for this unique ‘trojan silver bullet’ in phage therapy insures that those bacteria that undergo a lysogenic lifestyle choice are destined to perish.

Bacteriocide Mode of Action

Copyright © 2002 The Rowland Institute at Harvard.
Last modified Thursday, October 09, 2003.