Researchers Identify a New Class of Antibiotic Candidates

MIT researchers have discovered a class of compounds that can kill a drug-resistant bacterium that causes more than 10,000 deaths in the United States every year.

The researchers showed that these compounds could kill methicillin-resistant Staphylococcus aureus (MRSA) grown in a lab dish and in two mouse models of MRSA infection. The compounds also show very low toxicity against human cells, making them particularly good drug candidates.

A key innovation of the new study is that the researchers were also able to figure out what kinds of information the deep-learning model was using to make its antibiotic potency predictions. This knowledge could help researchers to design additional drugs that might work even better than the ones identified by the model.

Over the past several years, James Collins and his colleagues  have begun using deep learning to try to find new antibiotics. Their work has yielded potential drugs against Acinetobacter baumannii, a bacterium that is often found in hospitals, and many other drug-resistant bacteria.

These compounds were identified using deep learning models that can learn to identify chemical structures that are associated with antimicrobial activity. These models then sift through millions of other compounds, generating predictions of which ones may have strong antimicrobial activity.

First, the researchers trained a deep learning model using substantially expanded datasets. They generated this training data by testing about 39,000 compounds for antibiotic activity against MRSA, and then fed this data, plus information on the chemical structures of the compounds, into the model.

To figure out how the model was making its predictions, the researchers adapted a search algorithm that allowed the model to generate not only an estimate of each molecule’s antimicrobial activity, but also a prediction for which substructures of the molecule likely account for that activity.

Using this collection of models, the researchers screened about 12 million compounds, all of which are commercially available. From this collection, the models identified compounds from five different classes, based on chemical substructures within the molecules, that were predicted to be active against MRSA.

Experiments revealed that the compounds appear to kill bacteria by disrupting their ability to maintain an electrochemical gradient across their cell membranes. This gradient is needed for many critical cell functions, including the ability to produce ATP (molecules that cells use to store energy). 

“We have pretty strong evidence that this new structural class is active against Gram-positive pathogens by selectively dissipating the proton motive force in bacteria,” Wong says. “The molecules are attacking bacterial cell membranes selectively, in a way that does not incur substantial damage in human cell membranes. Our substantially augmented deep learning approach allowed us to predict this new structural class of antibiotics and enabled the finding that it is not toxic against human cells.”

“We are already leveraging similar approaches based on chemical substructures to design compounds de novo, and of course, we can readily adopt this approach out of the box to discover new classes of antibiotics against different pathogens,” Wong says.

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Sources:

Materials provided by Massachusetts Institute of Technology. Original written by Anne Trafton. Note: Content may be edited for style and length.

Felix Wong, Erica J. Zheng, Jacqueline A. Valeri, Nina M. Donghia, Melis N. Anahtar, Satotaka Omori, Alicia Li, Andres Cubillos-Ruiz, Aarti Krishnan, Wengong Jin, Abigail L. Manson, Jens Friedrichs, Ralf Helbig, Behnoush Hajian, Dawid K. Fiejtek, Florence F. Wagner, Holly H. Soutter, Ashlee M. Earl, Jonathan M. Stokes, Lars D. Renner, James J. Collins. Discovery of a structural class of antibiotics with explainable deep learning. Nature, 2023; DOI: 10.1038/s41586-023-06887-8

Massachusetts Institute of Technology. “Using AI, researchers identify a new class of antibiotic candidates.” ScienceDaily. ScienceDaily, 21 December 2023. <www.sciencedaily.com/releases/2023/12/231221012744.htm>.

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