Monday, 3 February 2014

Bacteria: Good and Bad and how to tell them apart

“I love bacteria because they remind me of God,” said the professor. He was religious and the head of the department of microbiology and biotechnology in Tel-Aviv University, explaining how religion and science can thrive together. “Bacteria are everywhere, you cannot see them and they can do ANYTHING – just like God”, he exclaimed.

Indeed bacteria are everywhere and they are definitely in our bodies covering our skin and lining our intestines, giving us our distinctive smell, eating away our dead cells and share our food. They provide us with valuable source of vitamins that cannot be obtained otherwise and they protect us from infections of other microorganisms. Some of us call them ‘good bacteria’ to differentiate our helpful little friends from the dangerous disease causing microbes. Our ‘friendly bacteria’ are actually symbiotic and opportunistic at the same time. We are dependent on our flora as much as under its’ threat.
Try to remember when was the last time you were prescribed a course of antibiotics. How did you feel?

I have been on such a course only three weeks ago, augmentin it was, a generic brand, and in a way I was relieved the manufacturer was not one of our clients (so I did not have to fill an adverse event form). Nevertheless, I was unwell. The antibiotics killed the bacteria on the lining of my gut affecting digestion and making me uncomfortable (forgive me for not giving more detail). It is a well-known side-effect that made me ponder over a tub of yoghurt, why not try and make targeted antibiotics? Wouldn’t it be grand if you could target bacteria causing disease and spare whole body’s flora? If we could differentiate good bacteria from bad?

What are bacteriophages?
Bacteriophages are viruses that propagate by infecting bacteria, their hexapods land onto their prey (Figure 1) and inject their DNA into the bacteria, giving it orders to multiply bacteriophages until the bacteria bursts, the progeny moves on to the next bacteria and so on. Bacteriophages are specific to a bacteria strain which gives them a potential to be employed as targeted antibiotics.

It is intuitive that we could utilise the specific power of bacteriophages into treating specific infections, but for some reason the technology has not been taken by the western world.

Phage treatment has been approved and in use in Russia and Georgia since the 1920s. It actually had been in use before penicillin was even discovered in 1928. However, somehow the fear of viruses and the excitement over chemicals has led to antibiotics being developed and widely used, and now we are facing a possible crisis of multiple drug resistant strains of bacteria (MDR). Some call MDR risk ‘the perfect storm’, with only a handful of new antibiotics developed since the 1980s, we are not prepared for the next outbreak.

At the Eliava institute in Tbilisi, Georgia, infections are being treated with bacteriophages.  For example, a case of tonsillitis is treated by gargling a bacteriophage broth and the patient is cured in 6 hours, no antibiotics involved.  In the UK a seven day antibiotics course is the standard of care.

Figure 1 Bacteriophages T4 sitting on a bacteria injecting their DNA into it (electron microscopy image Science museum),
What are the difficulties in producing bacteriophage based antibiotics?
First of all safety, the use of an entity that self-replicates and have the ability to evolve is difficult to regulate as a fixed chemical entity or biologic. Bacteria are likely to develop resistance to bacteriophages. When such a resistance develops it is likely that the bacteriophages will mutate accordingly, but that may cause issues with produced batches and regulation in mass production.

Formulation issues - you can’t get bacteriophages through our digestive tract, how can we bring them to their target? Can bacteriophage be inhaled for treatment of tuberculosis?  

Another issue with bacteriophages is that they cause bacterial lysis that releases endotoxins. These are toxic to patient and may cause severe side effects such as fever. 

Bacteriophages can be genetically modified to not lyse their target bacteria so one virus would kill one bacteria without bursting its walls. The dead bacteria will then be cleared by the immune system, also such attenuated bacteriophage would be easier to regulate. Just like the use of attenuated viruses in vaccines.

The main reason is a general lack of interest in developing antibiotics because of low return on investment (until there is an outbreak).

Bacteriophages have been used in the western world, for the invention of the probably the most profitable drug ever made.

In the 1990s the phage display technology was invented and utilised by Cambridge Antibody Technologies (CAT) and BASF. The scientists at CAT engineered bacteriophages to express antibody segments and used the ability of bacteriophage bacteriophages to mutate to create many different antibodies, called a phage display library. This library was reacted against TNFα (Tumor Necrosis Factor), the best matching antibody was chosen, cloned and mass produced as a humanised monoclonal antibody. Manufacturing and marketing were given to Abbot, and the brand Humira was named.  Humira is widely used to treat psoriasis, ankylosing spondylitis (AS) rheumatoid arthritis (RA), ulcerative colitis and Crohn’s disease.

The next most likely development in modern medicine will have to be a targeted antibiotic, maybe a bacteriophage? What do you think?
Figure 2 bacterial culture killed by bacteriophages (Wikipedia). Bacteria –white. Hole formed by dead bacteria in the middle.

Dr Shai Senderovich is a Research Executive at Branding Science,
Any opinions in this article belong to the author and do not represent Branding-Science.

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