Cinnamobactins is a New Mechanistic Class of Antibiotics Discovered with the Inspirations from Bacteriophage and Artificial Intelligence

Abstract

Antibiotic discovery faces a unique challenge after stagnating for many years. Inspired by bacteriophages, we chose bacterial nucleoid-associated protein HU as the target for drug screening. After identified a new HU inhibitor Belinostat, we then expanded the compound library using optimization from Artificial Intelligence (AI) and eventually identified a new class of HU-targeting antibiotics we term the cinnamobactins. Cinnamobactins are cinnamic-hydroxamic-acid derivatives (CHADs) that include two commercially available anti-cancer drugs Belinostat and Panobinostat, two investigational drugs Dacinostat and Pracinostat amongst other CHADs. Through the inhibition of the HU-DNA interaction, cinnamobactins cause nucleoid deformation and prevent bacterial division. We demonstrated their efficacy against a range of bacterial pathogens and in treating the superficial infections in mouse models. Notably, we also identified the natural product cinnamaldehyde as a member of cinnamobactins. Our findings suggest that a phage-based and AI-assisted approach presents an attractive route for antibiotic discovery.

Note:

Funding Information: This project is supported by the National Key R&D Program of China (2021YFA1301201 and 2021YFC2600200), the National Natural Science Foundation of China (32270151) and key research and development plan of Shaanxi Province (2021ZDLSF01-10).

Declaration of Interests: Bing Liu and other authors filed patent applications with the Chinese Appl. NO. 202110448865.4, 202310650575.7 and PCT/CN2022/085168, and U.S. Appl. No. 17/860, 889.

Ethical Approval Statement: The animal tests were performed at Biobank, the first affiliated hospital of Xi’an Jiaotong University, with approval from the Committee of Animal Ethics (Approval NO. 2021-1513).

Keywords: Antibiotics, Artificial Intelligence, Belinostat, Panobinostat, Dacinostat, Pracinostat, Cinnamic-hydroxamic-acid derivative, Cinnamobactin, Cinnamaldehyde