A Novel Biotechnological Approach to Combatting Drug Resistance

The rapid appearance of antimicrobial resistance and a significant slowdown in the development of new antibiotics have been recognized as a global medical emergency since the 1990s. Approaches to slow down, prevent or abolish such resistance are therefore urgently needed. To help address this, NIGMS recently funded the MIT Center for Integrative Synthetic Biology Link to external Web site led by Ron Weiss Link to external Web site. By integrating systems biology approaches with synthetic biology techniques, the center is deepening our understanding of complex and infectious diseases and developing the next generation of potential therapeutics.

Programmable remodeling of a microbial consortium. Credit: Robert James Citorik
Programmable remodeling of a microbial consortium. Credit: Robert James Citorik

In an article published recently in Nature Biotechnology Link to external Web site, a center team led by Timothy K. Lu Link to external Web site reported a proof-of-principle synthetic biology solution to treating bacterial infections and overcoming resistance. The team showed the applicability of the CRISPR-Cas9 technology to three major mechanisms of resistance—natural or intrinsic resistance, mutational resistance and extrachromosomal or acquired resistance—by specifically targeting chromosomal gene resistance, a single point mutant over wild-type and genes on an acquired plasmid. Survival rates of infected honeycomb moth larvae showed encouraging results for the feasibility of this approach in vivo.

Lu and coworkers pushed the application even further by selectively removing one bacterial strain in a synthetic microbial consortium. This exciting application of the CRISPR-Cas9 technology has important therapeutic implications for overcoming a critical limitation of antibiotic treatment, the inability to differentiate between pathogenic and commensal bacteria. This is crucial if one considers the beneficial role of human microbiota in human health. The ability to selectively modify the composition of a microbial consortium will enable functional studies of host-microbial symbioses and therapeutic approaches to microbial-associated diseases as well as to rebalancing environmentally or disease-perturbed microbiota.

This work was partly supported with funding to Timothy K. Lu through National Centers for Systems Biology grant P50GM098792 and to Robert J. Citorik by the MIT Biotechnology Predoctoral Training Program Link to external Web site grant T32GM008334.

Citorik RJ, Mimee M, Lu TK, Sequence-specific antimicrobials using efficiently delivered RNA-guided nucleases. Nature Biotechnology, 2014 Sept 21; 32(9): online (PMCID: PMC4237163)

For additional information, contact Barbara Gerratana.