Stamping Out Antibiotic Resistance

Imagine being able to diagnose a patient with a bacterial infection that is highly resistant to antibiotics, and knowing that it can be effectively treated as soon as the results leave your lab. This dream could soon be a reality if MIT and Harvard researchers have anything to do with it – they’re working to create entirely customizable antimicrobials, which can spot drug resistance genes and wipe them out. The method has already shown its potential, improving survival in an initial trial using an animal infection model.

The WHO has deemed antibiotic resistance a serious and worldwide threat to public health, predicting that without intervention, we could be headed for a “post-antibiotic era” (2) – so a method that removes such microbes from the gene pool could be a game changer. We spoke with Timothy Lu, associate professor of biological and electrical engineering and computer science at MIT, about developing this highly specific system and its potential to battle superbugs.

How did you get started?

Well, most antibiotics in use are broad spectrum, which leads to unwanted side effects such as Clostridium difficile overgrowth and the development of antibiotic resistance – an increasing problem. We decided to develop targeted agents that can kill bacteria based on their genetic content, with the main goal being to focus the therapy only on pathogenic bacteria. We designed a system – based on a gene editing method known as CRISPR/Cas – that can essentially act as genomic scissors, cutting any arbitrary piece of DNA. We used it to selectively target and kill bacteria that carry undesirable genes, such as antibiotic resistance and virulence genes.

Any surprises?

We showed that our targeted antimicrobials could discriminate between bacteria with a difference of only one DNA base – this was so exciting to us! They could also be multiplexed to target multiple undesirable genes simultaneously. Further surprises came when we realized that the antimicrobials could be repurposed for use as a diagnostic for pathogenic genes – something that could prove useful for rapid point-of-care diagnostics. Finally, their ability to target pathogenic genes carried both on plasmids and in bacterial genomes, is also very valuable.

What’s next?

We aim to extend our platform to other pathogens, test it in mammalian preclinical models, and continue to improve its efficacy and delivery modalities. We believe that new technologies such as ours will play an increasingly important role in addressing antibiotic resistance. In particular, we want to create a new paradigm for personalized and targeted therapies where the causative bacteria in infections are rapidly diagnosed, allowing for the use of the most efficacious and targeted antimicrobial. At the moment, clinical practice allows for the indiscriminate use of broad spectrum antibiotics, and this needs to stop.

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References

1. R. J. Citorik et al., “Sequence-Specific Antimicrobials Using Efficiently Delivered RNA- Guided Nucleases”, Nat. Biotechnol., [epub ahead of print] (2014). doi:10.1038/nbt.3011.
2. WHO “Antimicrobial Resistance: Global Report on Surveillance 2014”, April 2014.

About the Author(s)

Roisin McGuigan

I have an extensive academic background in the life sciences, having studied forensic biology and human medical genetics in my time at Strathclyde and Glasgow Universities. My research, data presentation and bioinformatics skills plus my ‘wet lab’ experience have been a superb grounding for my role as an Associate Editor at Texere Publishing. The job allows me to utilize my hard-learned academic skills and experience in my current position within an exciting and contemporary publishing company.

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