Artificial Intelligence-Crafted Compounds Display Strong Effectiveness Against Bacteria Resistant to Treatment
Scientists from MIT and collaborators, in collaboration with the nonprofit biotech organization Phare Bio, have made a significant breakthrough in the fight against drug-resistant bacteria. In a paper published in Cell, they detail the design of novel antibiotics capable of combating drug-resistant Neisseria gonorrhoeae and multi-drug-resistant Staphylococcus aureus (MRSA).
The team, led by MIT scientist James Collins, used generative AI to design over 36 million possible compounds and computationally screened them for antimicrobial properties. From this vast pool, they identified a fragment they dubbed F1, which showed promising activity against N. gonorrhoeae.
The researchers used two different approaches to design these antibiotics. One directed the algorithms to design molecules based on a specific chemical fragment with antimicrobial activity, while the other allowed the algorithms to freely generate molecules without requiring a specific fragment.
The fragment-directed approach was used to identify molecules that could potentially kill N. gonorrhoeae, the bacterium that causes gonorrhea. The top candidate, DN1, successfully treated a MRSA skin infection in a mouse model. On the other hand, NG1, another top candidate, effectively killed N. gonorrhoeae in both cells and a mouse model of drug-resistant gonorrhea.
NG1 interacts with a protein called LptA, a novel drug target involved in the synthesis of the bacterial outer membrane. DN1, however, seems to interfere with bacterial cell membranes, but its interactions are not limited to a specific protein.
The top candidates from the screening are structurally distinct from existing antibiotics and use novel mechanisms that disrupt bacterial cell membranes. Phare Bio is now working on further modifying NG1 and DN1 to make them suitable for additional testing.
In a separate group of studies, the scientists used the unconstrained design approach to design novel molecules that target drug-resistant S. aureus. The team filtered these down to about 90 compounds, and six showed strong antibacterial activity against multidrug-resistant S. aureus in cells.
These findings represent a significant step forward in the development of new antibiotics to combat drug-resistant bacteria. The researchers are optimistic about the potential of these new antibiotics to address one of the most pressing global health challenges of our time.
