Bacteriophages: a wealth of potential applications
The emergence of bacteria resistant to multiple antibiotics and the slow pace of development ofnew antibiotics have placed the spotlight back on a biotechnology discovered in the 1910s, based on the use of bacteriophages. But what exactly are these natural bacteria-consuming predators which today offer a wealth of potential applications for human, animal and plant health purposes?
Last July, Lesaffre acquired a shareholding in Intralytix, an American biotechnology company, which aims to develop and market bacteriophage-based products beneficial to human health and useful in numerous other fields. We take a closer look at this biological microentity discovered at the very end 19th century;
Observed and photographed in 1940 (see photo) thanks to the invention of the electron microscope, bacteriophages (from the Greek word phago which means “eat”) are viruses specific to bacteria. For every known bacteria variety, there is at least one identified bacteriophage. First appearing several billion years ago along with the bacteria, bacteriophages (often referred to as phages) account for the planet’s largest biomass: there are believed to be between 10 and 100 times more of them than bacteria, i.e. approximately 1031. Present in every ecosystem (water, soil, plants, people, etc.) they contribute to the replacement and regulation of bacterial populations. As a species, humans host many phages, particularly in the skin, the mucous membranes and above all the digestive tract, where more than 100 kinds of different phages have been identified, which could play a role in the dynamics and diversity of intestinal bacterial populations and therefore the health of our intestinal flora(1).
Bacteriophage: how it works
Each bacteriophage is specific to a bacterial species but they also attack one or several strains of the same species. This species-specific characteristic prevents the phages from modifying other species present in the environment. How does a phage go about destroying the target bacterium? After attaching itself to the bacterium’s surface using specific receptors, the phage injects its DNA and uses the bacterium’s own internal mechanism for its own benefit, to reproduce and multiply. At the end of the process known as the lytic cycle(2) (less than 30 minutes), the bacterium bursts and several dozen new phages – all identical to the first – are freed into the local environment and are therefore available to attack other bacteria of the same species. Phages, once their target is destroyed, are able to survive in the natural environment even in poor conditions. However, their survival should have limits but they are still not very well known.
Potential uses in human medicine
Thanks to their bactericidal characteristics, bacteriophages have shown themselves to be promising alternatives to antibiotics, especially as they are able to attack bacteria which have become resistant to anti-bacterial treatments. However, bacteriophage therapy(3) is only currently allowed in human medicine in certain countries such as Poland, Georgia and Russia. In other countries (France, Germany, Belgium, the United States, Canada, Israel or Australia), it is only used exceptionally in cases involving therapeutic impasses and for compassionate use, this particular use being based on the Helsinki Declaration, solely under the doctor’s liability, and with the patient’s consent. The range of infections treated by bacteriophage therapy, whether authorised or tolerated on an exceptional basis, is quite wide (including the treatment of infected wounds, gastro-intestinal infections, infections of the respiratory, osteoarticular, urinary and genital tracts, etc.). Currently, the application of regulations concerning medicines is not entirely adapted to the industrial development of phages. Furthermore, Marketing Authorisation procedures are designed for inert and fixed drugs and do not allow for the regular launch of phage cocktails(4) which must be adapted according to the bacteria. A position will need to be established concerning their use as a therapeutic agent and bio-medicine, particularly in Europe.
Applications in the food production chain
From the farm to the fork, foodstuffs undergo numerous processing and storage phases which are all key points for possible contaminations. The use of bacteriophages in the food industry recently became a new option for the biocontrol of pathogens potentially present in food (fish, meat, cheese, milk, etc.). In the United States, the “Food and Drug Administration” (FDA) has authorised phage-based products for decontamination purposes in the food industry. Intralytix was the first company in the world to receive GRAS approval (Generally Recognized As Safe) from the FDA for its ListShield product (a phage cocktail making it possible to eliminate the bacteria Listeria monocytogenes from contaminated surfaces or fresh food).
Further upstream, the use of bacteriophages may also provide a biological alternative to the chemical substances currently used in agriculture (pesticides, antibiotics). Concerning the cultures, two products in particular are marketed in the United States targeting two tomato pathogens. Numerous studies into specific veterinary uses have been conducted over the last 30 years on laboratory animals, particularly mice but also livestock including poultry, lambs, piglets and calves. Certain veterinary treatments are currently marketed around the world. In the United States, a drug for veterinary use is being produced and marketed to combat dermatitis in dogs. Other products are mainly intended for livestock, such as INT-401™ (to combat Clostridium perfringens) from Intralytix used for poultry. These products are currently marketed in the United States, Canada and Israel but are not authorised in Europe however.
Faced with constantly increasing bacterial resistance to antibiotics and pressure from consumers to reduce the level of antibiotics used in the human food chain, bacteriophages offer one of the most promising alternatives. The large-scale research programmes currently carried out worldwide and the vital changes in legislation will make it possible to facilitate the use of bacteriophage therapy in human and animal health, something which has been successfully used for more than 90 years in Georgia (www.sesoignerengeorgie.com).
(1) intestinal flora: all of the micro-organisms (bacteria, yeast, fungus, viruses) living in the intestine
(2) lytic cycle: only those bacteriophages which multiply via a lytic cycle are considered for therapeutic purposes as they can act by destroying bacteria they infected
(3) bacteriophage therapy: a therapy which uses phages to treat bacterial infections
(4) phage cocktail: to avoid resistance developing (although this appears less problematic than with antibiotics) and to guarantee optimal therapeutic effectiveness, it is recommended that the product contains at least 3 different phages acting on the bacterial strain to be treated.