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The Problem

Our iGEM project aims to tackle the emerging problem of antibiotic resistance by leveraging the power of natural selection under selective pressure. It is known that higher exposure to antibiotics leads to the resistance against that antibiotic in bacterial populations.

Anti microbial peptides are small protein molecules that have been shown to have anti-microbial activity. They are also also known to exhibit lower tendency to develop antibiotic resistance. Recently, However, it has also been reported that a prolonged exposure to anti-microbial peptides could also lead to the emergence of resistance in bacteria

Our Solution

Here, we come up with a solution to this problem. We will synthesize a bacterial system that:

1. Senses the cell density of pathogenic bacteria
2. Our system releases anti-microbial peptides which kill pathogens, when it has sensed high cell density
3. As the population goes down we release a peptide that neutralizes the activity of anti-microbial peptides, resulting into a stress free environment.The stress-free environment would be favourable to the wild type compared to the mutants which have developed antibiotic resistance

Consequentially this will lead to a population of predominantly wild type bacteria. Again, as the population of wild type goes up, the same cycle of steps 1-3 is repeated. After few cycles, the pathogens should be eliminated.

The system we propose will use an anti microbial peptide Alyteserin, which has bactericidal effects. Alyteserin has a lethal effect on gram negative bacteria.[Ref. 2] We have designed a novel short peptide sequence(which shall be called NAly from herein). Molecular Dynamics simulations of Alyteserin and NAly have been performed under various conditions and conformations, and we have found that the two peptides interact favourably.

The pathogen of interest, which has to be a gram negative bacterium in this case was chosen to be E.Coli. We chose E.Coli for its ease of availability in a laboratory setting, but Alyteserin is a broad antimicrobial peptide and is effective against a wide range of gram negative bacteria including E.Coli and Salmonella Typhi.

We chose the carrier of the AMP to be Lactococcus Lactis, for several reasons. L.lactis is a gram positive bacterium. This ensures that the AMP would not have lethal effects on L. lactis itself. Also, L.lactis is a non-pathogenic bacteria, and will not elicit an inflammatory response from the human immune system. Developing the genetic circuit for timed release of AMP and its inhibitory molecule inside L.lactis will provide more scope in the future for developement of a robust drug delivery system.