Sunday, July 19, 2015

Advances in Antibiotic Alternatives for Better Health: Promising Research for "Weeding" Bacterial Communities

Antibiotic treatment can be like weeding a garden with
pesticides that kill everything. Scientists are working on
more targeted approaches, like pulling individual weeds.
The discovery and production of antibiotics, which was certainly one of the most significant medical breakthroughs of the twentieth century, has not been without its shortcomings. One shortcoming that has gained recent attention is the lack of bacterial specificity. Antibiotics are often used to prevent or treat specific bacterial infections, but they often target a range of bacteria, many of which are actually beneficial to human health.

The broad destruction of bacteria within a human ecosystem can open the niche up to other harmful bacteria, and can cause long lasting effects due to altered bacterial recolonization. This is a similar effect to covering your entire garden with harsh herbicides to kill the weeds. You will certainly kill the weeds, but you will also destroy the beneficial flowers and vegetables. Because the resulting garden bed is an open patch of dirt, other plants will start to recolonize, including other weeds, leaving the garden very different from how it started. This is why other approaches are generally used in gardening.

So how would you treat your garden for weeds instead of dousing the entire thing in deadly chemicals? Many would consider a more targeted approach of getting down and pulling out the weeds while leaving the flowers and plants. This targeted approach has similarly become the goal of clinicians in treating bacterial infections. It would be ideal to only kill the harmful bacteria while leaving the beneficial bacteria. Unfortunately antibiotics don't give us that kind of treatment resolution, so researchers have been working on developing new approaches to treating these infections. One cool technology, reported by Gomma et al, uses CRISPR genome targeting to only kill specific bacteria.

The foundation of this targeted technology is the CRISPR system of bacterial immunity. CRISPR arrays act as a sort of adaptive immune response in which genomic sequences of invading bacteriophages, plasmids, etc are recorded after the infected agent is repelled. This sequence is used during the next infection to quickly target and destroy that genomic agent, thereby protecting the bacteria during an infection. For more of a refresher, check this post out for more details.

This is the idea behind the paper (Figure 1). The group is trying to remove individual
bacteria (green) without affecting the other community members.

The research group led by Gomma et al used this system, but altered it to target bacterial genomic sequences instead of viruses or plasmids. The result is the destruction of that bacteria. The great part about this is the incorporation of sequence specificity because the bacteria will be killed only if it contains the sequence targeted by the CRISPR. This means it could act like the weeding tool that we wanted above!

The paper goes into the details of validating and optimizing their system, but we are not going to get into that here (read the paper for that info). Ultimately the experimental highlight is their series of tests for destruction specificity of specific bacteria. The group shows that they are able to design their system to target very specific genomic regions to the point where it will destroy one strain of E. coli, and not a related strain that is over 99% identical. This was done in a co-culture system (the bacteria were mixed together), as well as when the bacteria were separate. They also showed high specificity in other bacteria.

Bacteriophages offer a delivery method for the CRISPR
based drug described here. Source
This study is really cool, but they did not report the experiment I most hoped they would do. They did not report using their system in a mouse gut microbiome system to show that they could knock out specific members of the bacterial community. This would be a huge deal for the microbiome field because it would present amazing methodological opportunities to knock out bacteria to see how they affect the microbiome and animal host health. This would be difficult and require a lot more time/funding so I'm sure it is in the works and we are going to have to sit tight and wait.

One of the big hurdles the authors mention is that of delivering the drug to its target bacteria. It is one thing to get it to the bacteria in lab bench cultures, but it is another to get it to the bacteria inside a human or other animal. They rightly mention nanoparticles or bacteriophages as potential vectors for delivery. I agree that this is a good idea and I am really excited to see how it turns out.

Like most studies, this is still a work in progress and the group has some obstacles to overcome. Despite this, the research group presents a really cool technology with a lot of promise and broad applications in medicine, industry (killing contaminating bacteria), and microbiome research. I am excited to see how this research program moves forward, and how effectively it allows us to do some specific "microbial gardening" in the clinic.

Works Cited

Gomaa, A., Klumpe, H., Luo, M., Selle, K., Barrangou, R., & Beisel, C. (2014). Programmable Removal of Bacterial Strains by Use of Genome-Targeting CRISPR-Cas Systems mBio, 5 (1) DOI: 10.1128/mBio.00928-13

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