Team:IISc-Bangalore/Description

Overview

The tragedy of the antibiotic

In 1929, a largely unnoticed paper appeared in the British Journal of Experimental Pathology by a less known army doctor named Alexander Fleming highlighting the use of a fungally isolated compound as an antibacterial. This compound was Penicillin, a molecule that single-handedly revolutionized the way infections were treated because of its extreme stability and ease of isolation. Antibiotics soon became a buzzword with an increasingly large number of such compounds being discovered by multiple groups over the world.

At the same time, in another part of the world, a long known cure for bacterial infections started losing its charm. This cure used phages - which are viruses that infect bacteria - to eliminate bacterial pathogens. However, the ease with which antibiotics could be modified (chemically) and characterized for negative effects completely knocked phage therapy off the treatment map.



While these events unrolled, a new and critical problem started coming into the picture, that of antibiotic resistance. Bacteria are constantly evolving, adapting creatures. Over generations, with the accumulation of mutations over marginally fitter phenotypes, they are capable of evolving into an organism that is significantly resistant to the antibiotic.

In January 2018, right when we were on a lookout for idea, a very interesting article[1] appeared on the website of The Bureau of Investigative Journalism. This article mentioned colistin - a last resort antibiotic - which was turning out to be a major cause of worry for people both in India and the rest of the world. After a lot more research into this direction, we realised the true magnitude of the problem.

Colistin belongs to the polymyxin class of antibiotics, a class which is given the highest priority in the WHO list of critically important antimicrobials[2]. In spite of this, it is being used by poultry farmers across the country (and abroad) as a growth promoter for increasing the yield of meat.

WHO list of critically important antimicrobials

After a quick search we found at least three manufacturers in India selling colistin or colistin containing additives for chicken feed. One manufacturer even claimed that colistin "does not lead to resistance by bacterial selection". The stark difference in awareness and concerns for antibiotic resistance between these two groups was surprising.

A possible solution?

Phages come out as a seemingly obvious alternative to antibiotics when one tries to look at the bigger picture. The reasoning being the following:

  • Being biological agents, they can co-evolve in a continuous arms race against bacteria.
  • They increase in number specifically at the site of infection - a process referred to as autodosing thus preventing any side affects from non-specific targeting.
  • The process of phage discovery is much faster and much more straightforward than the process of antibiotic discovery.

On close analysis, however, it is revealed that this methodology itself is not free of a wide variety of problems. Some of the most prominent ones being:

  • While they do mutate and co-evolve, the rate of phage evolution is not fast enough to be within the lifetime of a single patient. As such they also suffer from the same integral problem as antibiotics.
  • Phages, being viruses, are not perceived in a very positive manner among the general populus.
  • The rules and regulations for administration of phages are neither clear nor very reasonable considering they are a completely new modality for treatment.
  • Both phages and antibiotics lead to bacterial endotoxin release, an especially severe problem for patients with possibilities of multi-organ failure

PhageShift as a project started with the following goals in mind

Goal 1

To engineer a phage that is either less prone to become obsolete due to bacterial resistance or improves the performance of conventional antibiotics


Phage Antibiotic Complementarity Mediated Antimicrobial Network and a software to implement it

To make the public more aware about phages and how they might be a possible solution to the antibiotic resistance crisis


Goal 2

Goal 3

To survey the current policy on phage therapeutics and come up with the necessary changes required to make phage therapy legally acceptable


To develop a system for rapid development of phage cocktails against resistant bacteria


Accelerated Phage Evolution System

Goal 4

While working on these goals, we realised two more integral problems with phage therapy

through our interactions with Medical professionals

through our interaction with GangaGen



Problem #1

Both antibiotic and phage treatment leads to endotoxin release

Our solution


Phage Assisted Immune Recruitment

Problem #2

It is not easy to characterise the dosage of phage as opposed to antibiotics

Our solution


An attempt at finding dosage for a complex drug target interaction


References

[1]https://www.thebureauinvestigates.com/stories/2018-01-30/a-game-of-chicken-how-indian-poultry-farming-is-creating-global-superbugs
[2]World Health Organization. "Critically important antimicrobials for human medicine: ranking of antimicrobial agents for risk management of antimicrobial resistance due to non-human use." (2017).