Bacteriophage: The alternative solution to AGPs

Antibiotics were first used in the 1940s and were considered the best invention of the 20^th century. However, antibiotic-resistant bacteria quickly emerged after only a few years. Currently in 2020, a multidrug-resistant bacteria, known as the “Superbug,” is threatening the world.

In 2014, the World Health Organization warned of the danger regarding the use of antibiotics in livestock feed, stating, “if antibiotics are added to livestock feed, it can accumulate in the animal and eventually affect the human immune system through the food chain.”

Ban on antibiotics

To reduce the use of antibiotics, the European Union first banned the use of AGPs in 2006. In Korea, all growth promoters have been prohibited since the second half of 2011. In 2017, the US Food and Drug Administration (FDA) proposed new guidelines to ban AGPs, and allow only those antibiotics prescribed by veterinarians for disease treatment considering animal welfare and health.

However, banning the use of AGPs in livestock led to problems such as lower feed efficiency, impaired growth rate, and higher mortality. An alternative to AGPs is needed for both efficient growth and bacterial disease control in livestock animals.

Therefore, what are the other options that can effectively impede problems caused by both antibiotic resistance and livestock disease?

Bacteriophage: A natural “bacteria eater”

A bacteriophage is a natural antibacterial entity that has been used before antibiotics were even discovered. As antibiotic-resistant bacteria emerged the efficacy of antibiotics was reduced, along with other health concerns threatening both human and animals. Since then, bacteriophages have attracted much attention as a potential alternative solution. So what are the characteristics and efficacies of bacteriophages?

A bacteriophage is a virus that targets bacteria. Unlike other harmful viruses, bacteriophages specifically recognise and attack only bacteria, and do not affect or harm humans or other living organisms. It has the largest number of particles as individuals on Earth (10³¹ particles) and can exist in various environments such as seawater, freshwater, soil, and food.

Bacteriophage infects bacteria by attaching to the bacterial cell membrane and injecting its genetic information into the bacterial host. Thereafter, bacteriophage proliferates using bacterial host machinery, leading to lysis of the bacteria via either lytic or lysogenic cycle. In this action, bacteria is killed by bacteriophage (Figure 1). In contrast to antibiotics which can be non-selective, bacteriophages have high specificity to the target hosts. Because bacteriophages exist abundantly in nature, they can be developed within a relatively short period of time and at a lower cost than conventional antibiotic development.

Figure 1 – Life cycle of lytic bacteriophage. Bacteriophage can destroy its target bacteria effectively, and the whole process only takes approximately 20 minutes.

Safety regarding the use of bacteriophages has been verified by the US FDA, and was approved in 2006 with recognition as GRAS (Generally Recognised as safe).

Given these advantages, the potential for bacteriophage application in livestock is attracting more attention. Optipharm Inc. is putting every effort in to the development and commercialisation of a new bacteriophage product called ProBe-Bac.

Optipharm’s bacteriophage solution

The product was developed as a joint venture between Optipharm Inc. and Pathway Intermediates with the aim to provide a solution beyond pathogen control. Bacteriophage settles in the animal intestine and controls the population balance of gut microflora by reducing the number of specific pathogenic microorganisms, promoting animal growth, and improving feed efficiency. When an animal is under stress, gut flora of the digestive system breaks down, favouring rapid proliferation of pathogenic bacteria which causes diarrhoea and lower feed efficiency. ProBe-Bac has been developed to control such problems (Figure 2).

There are 2 versions of the product: ProBe-Bac PE for poultry and ProBe-Bac SE for swine, each containing various bacteriophages.

1. ProBe-Bac PE targets diseases such as poultry typhoid, salmonellosis, and diarrhoea in poultry.
2. ProBe-Bac SE targets diseases in swine that cause systemic edema, colibacillosis, salmonellosis, and diarrhoea.

Bacteriophages from ProBe-Bac would settle in the animal intestine upon ingestion, which improve the intestinal environment, inhibit growth of harmful microorganisms, and boost feed efficiency.

Figure 2 -Mode of action with ProBe-Bac. Bacteriophages are supplemented to feed and introduced into the animals. They are able to control diseases by killing pathogenic bacteria.

Bacteriophage products and future plans

Optipharm is a company promoting biomedical solutions with the mission to enhance the quality of life. It conducts various studies with different specific aims, such as developing and producing bacteriophage products, diagnosing animal diseases, developing transgenic animals through genetic manipulation, and developing vaccines using Virus-like particles (VLPs). In terms of bacteriophage products, various products have already been developed in many forms and provided to animals with promising results. Compared to the existing bacteriophage products, the newly developed ProBe-Bac has improved stability with the addition of new sources that maximises the efficacy of controlling pathogenic bacteria.

Optipharm’s bacteriophages are isolated by researchers to ensure the superiority of their efficacy. The bacteriophages used are isolated from various environments, purified, and analysed to characterise each phage. They are carefully selected through morphology and genetic analysis. Stability studies are conducted at various pH and temperature ranges, and the ability to destroy bacteria is also verified. In addition, bacteriophages that show excellent efficacy are tested by direct administration to animals to assess their effectiveness in improving the intestinal environment, and overall parameters such as mortality, weight gain, and animal productivity.

Figure 3 – Optipharm has various bacteriophages that show high antibacterial activity. Optipharm has also been focusing on endolysin produced by bacteriophages.

Currently, the company has constructed a bacteriophage library with more than 300 master seeds that can effectively control pathogenic bacteria. 30 of the bacteriophages are registered for patents, and 11 are under process. In addition to animal disease control, these bacteriophages can be used to target zoonotic bacteria, foodborne pathogens, and human antibiotic-resistant bacteria. Based on the accumulated data of more than 200,000 diagnoses per year, it is possible to provide solutions to frequently occurring animal diseases as well as epidemic diseases. This gives the advantage of immediate application of the most appropriate bacteriophages should there be a livestock epidemic outbreak. The bacteriophage products demonstrate the possibility of replacing AGPs based on farm application tests, and are actively applied to animals for disease control. Optipharm will continue to work on improving public health by seeking novel solutions to reduce the usage of antibiotics and expand the range of products.

References are available on request