Microbiology
Combinatorial Genetics Enlisted in Search for New Antibiotic Drugs
As drug-resistant microbes render useless once effective antibiotics, a medical crisis is brewing that forces researchers to face anew an old question: where are those microbe-thwarting substances that surely must exist somewhere in nature or in the synthetic chemist's toolbox?
Adding a new way to tackle this problem is a study by Jonathan Blum, HMS postdoctoral fellow, and John Mekalanos, the Adele Lehman professor of microbiology and molecular genetics at HMS. With Simon Dove and Ann Hochschild, instructor and associate professor, respectively, in the department, the scientists present in the Feb. 25 Proceedings of the National Academy of Sciences a method that can identify inhibitors of essential processes in bacteria.
Conceptually, the technique resembles combinatorial chemistry, an approach widely used in drug discovery that is based on first creating libraries of diverse chemicals and then picking out the ones that do something interesting. Rather than chemically synthesizing nonpeptide molecules, however, the new approach exploits nature's ease at creating vast sequence diversity in peptides. In essence, it offers a low-tech version of a high-throughput screen that can be conducted by just a microbiologist with his petri dishes, without the need for chemists and robots.
Dubbed ABBIS (aptamer-based bacterial inhibition systems), the method uses a Trojan horse stratagem. It sneaks into bacteria a DNA library for random peptides, which then are expressed and, in some cases, kill the bacteria or halt their growth. This way, ABBIS manages to test in a simple experiment the 10 million substances contained in its library, whereas even a large commercial combinatorial chemistry library contains only about two million compounds.
"ABBIS has the potential to help us find new targets and inhibitors of those targets. It could become important for developing new kinds of antimicrobials," says Blum, who sees patients with AIDS and other infections at Massachusetts General Hospital in addition to his lab research.
ABBIS's power in the search for antibiotics is limited because peptides make poor drugs and converting them to a small-molecule drug remains difficult. Yet basic researchers can use the method with great flexibility for discovering inhibitors of their cellular process of interest.
FULL STORY
