Gene Therapy for Bacteria?

Many antibiotics in use today are effective against a broad range of bacteria. But their misuse has led to the development of multi-drug resistant organisms, so-called “superbugs.”

Timothy Lu and Chao Zhong (MIT) and Lei Chen and Yan Liang (L2Molecule.com)

“We were very frustrated with the fact that most broad-spectrum antibiotics are still being used, and we think that there are a lot of consequences associated with that,” said Timothy Lu, a biological and electrical engineer at the Massachusetts Institute of Technology. “Instead of trying to blast everything in the population, we wondered whether we could build antimicrobials that have sequence-specific effects.”

Taking advantage of phage-based delivery techniques developed in their lab, Lu’s group employed CRISPR-Cas—a system that bacteria use to prevent viral attack—to delete offending genes such as NDM-1, which imparts bacterial resistance to a broad range of beta-lactam antibiotics.

In a synthetic grouping of three strains of Escherichia coli with differing antibiotic-resistance profiles, the team was able to selectively target the strain they wanted using their new strategy, while leaving other bacteria intact (1).The group treated waxworm larvae infected with a harmful form of E. coli and are currently performing studies in mice.

Although this CRISPR-Cas system is simple and inexpensive to build, delivering the system efficiently into specific bacteria is not trivial. That’s the biggest barrier for commercial development as a therapeutic, Lu said. There are no phage-based delivery systems currently approved in the US for use in humans.

“Translating this work into a therapy will require the future development of methods for delivering these constructs. Nonetheless, this work represents a very interesting paradigm for antimicrobial ‘gene therapy’,” said Ahmad Khalil, assistant professor of biomedical engineering at Boston University, who was not involved with the research.

Another study by a separate group, published online in Nature Biotechnology, describes a similar approach to killing virulent, but not avirulent, Staphylococcus aureus (2).

Both groups have filed patents for their new targeting systems.

References

1. Citorik RJ, Mimee M, Lu TK. Sequence-specific antimicrobials using efficiently delivered RNA-guided nucleases. Nat Biotechnol. 2014 Sep 21. doi: 10.1038/nbt.3011. [Epub ahead of print]
2. Bikard D, Euler CW, Jiang W, Nussenzweig PM, Goldberg GW, Duportet X, Fischetti VA, Marraffini LA. Exploiting CRISPR-Cas nucleases to produce sequence-specific antimicrobials. Nat Biotechnol. 2014 Oct 5. doi: 10.1038/nbt.3043. [Epub ahead of print]



 Source: Biotechniques

Posted by Tim Sandle