CAMBRIDGE, Mass.—Using a machine-learning algorithm, Massachusetts Institute of Technology (MIT) researchers identified a new antibiotic compound earlier this year. In laboratory tests, the drug killed many of the world’s most problematic disease-causing bacteria, including some strains that are resistant to all known antibiotics. It also cleared infections in two different mouse models.
The computer model, which can screen more than a hundred million chemical compounds in a matter of days, is designed to pick out potential antibiotics that kill bacteria using different mechanisms than those of existing drugs.
“We wanted to develop a platform that would allow us to harness the power of artificial intelligence to usher in a new age of antibiotic drug discovery,” says James Collins, the Termeer Professor of Medical Engineering and Science in MIT’s Institute for Medical Engineering and Science and its Department of Biological Engineering. “Our approach revealed this amazing molecule, which is arguably one of the more powerful antibiotics that has been discovered.”
In their new study, the researchers also identified several other promising antibiotic candidates, which they plan to test further. They believe the model could also be used to design new drugs, based on what it has learned about chemical structures that enable drugs to kill bacteria.
“The machine-learning model can explore, in silico, large chemical spaces that can be prohibitively expensive for traditional experimental approaches,” says Regina Barzilay, the Delta Electronics Professor of Electrical Engineering and Computer Science in MIT’s Computer Science and Artificial Intelligence Laboratory.
Over the past few decades, very few new antibiotics have been developed, and most of those newly approved antibiotics are slightly different variants of existing drugs. Current methods for screening new antibiotics are often prohibitively costly, require a significant time investment, and are usually limited to a narrow spectrum of chemical diversity.
“We’re facing a growing crisis around antibiotic resistance, and this situation is being generated by both an increasing number of pathogens becoming resistant to existing antibiotics, and an anemic pipeline in the biotech and pharmaceutical industries for new antibiotics,” Collins comments.
The idea of using predictive computer models for in-silico screening is not new, but until now, these models were not sufficiently accurate to transform drug discovery, according to MIT. Previously, molecules were represented as vectors reflecting the presence or absence of certain chemical groups. However, the new neural networks can learn these representations automatically, mapping molecules into continuous vectors which are subsequently used to predict their properties.
In this case, the researchers designed their model to look for chemical features that make molecules effective at killing E. coli. To do so, they trained the model on about 2,500 molecules, including about 1,700 FDA-approved drugs and a set of 800 natural products with diverse structures and a wide range of bioactivities.
Once the model was trained, the researchers tested it on the Broad Institute’s Drug Repurposing Hub, a library of about 6,000 compounds. The model picked out one molecule that was predicted to have strong antibacterial activity and had a chemical structure different from any existing antibiotics. Using a different machine-learning model, the researchers also showed that this molecule would likely have low toxicity to human cells.
This molecule, which the researchers decided to call halicin, after the fictional artificial intelligence system from “2001: A Space Odyssey,” has been previously investigated as possible a diabetes drug. Preliminary studies suggest that halicin kills bacteria by disrupting their ability to maintain an electrochemical gradient across their cell membranes.
After identifying halicin, the researchers also used their model to screen more than 100 million molecules selected from the ZINC15 database, an online collection of about 1.5 billion chemical compounds. This screen, which took only three days, identified 23 candidates that were structurally dissimilar from existing antibiotics and predicted to be nontoxic to human cells.
The researchers also plan to use their model to design new antibiotics and to optimize existing molecules. For example, they could train the model to add features that would make a particular antibiotic target only certain bacteria, preventing it from killing beneficial bacteria in a patient’s digestive tract.
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Adapted from an article written by Anne Trafton for the MIT News Office
