Halicin Explained

Halicin (SU-3327) is an experimental drug that acts as an enzyme inhibitor of c-Jun N-terminal kinase (JNK).[1] [2] [3] Originally, it was researched for the treatment of diabetes,[4] but development was discontinued for this application due to poor results in testing. In 2019, this molecule was found by an artificial intelligence (AI) model to show antibiotic properties against a number of bacteria.

History

Halicin was previously known as SU-3327,[5] developed by a group of researchers from Burnham Institute for Medical Research, United States in 2009 for investigations into diabetes treatment.[4] Researchers named the molecule after the fictional artificial intelligence system Hal from 2001: A Space Odyssey.

Antibiotic properties

Halicin was identified by artificial intelligence researchers, including bioengineer James Collins, at the MIT Jameel Clinic in 2019 using an in silico deep learning approach, as a likely broad-spectrum antibiotic.[6] The process took just three days.[7] This likelihood was verified by in vitro cell culture testing, followed by in vivo tests in mice.[8] It showed activity against drug-resistant strains of Clostridiodes difficile, Acinetobacter baumannii, and Mycobacterium tuberculosis, with an unusual mechanism of action involving the sequestration of iron inside the bacterial cells, that thereby interferes with their ability to regulate the pH balance across the cell membrane properly. Since this is a different mode of action from most antibiotics, halicin retained activity against bacterial strains resistant to many commonly used drugs.[9]

Preliminary studies suggest that halicin kills bacteria by disrupting their ability to maintain an electrochemical gradient across their cell membranes. This gradient is necessary, among other functions, to produce adenosine triphosphate (ATP, molecules that cells use to store and transfer energy), so if the gradient breaks down, the cells die. This type of killing mechanism could be difficult for bacteria to develop resistance to.[10]

External links

Notes and References

  1. Augustine C, Cepinskas G, Fraser DD . Traumatic injury elicits JNK-mediated human astrocyte retraction in vitro . Neuroscience . 274 . 1–10 . August 2014 . 24838066 . 10.1016/j.neuroscience.2014.05.009 . 9498486 .
  2. Jang S, Javadov S . Inhibition of JNK aggravates the recovery of rat hearts after global ischemia: the role of mitochondrial JNK . PLOS ONE . 9 . 11 . e113526 . 2014 . 25423094 . 4244102 . 10.1371/journal.pone.0113526 . 2014PLoSO...9k3526J . free .
  3. Jang S, Yu LR, Abdelmegeed MA, Gao Y, Banerjee A, Song BJ . Critical role of c-jun N-terminal protein kinase in promoting mitochondrial dysfunction and acute liver injury . Redox Biology . 6 . 552–564 . December 2015 . 26491845 . 4625008 . 10.1016/j.redox.2015.09.040 .
  4. De SK, Stebbins JL, Chen LH, Riel-Mehan M, Machleidt T, Dahl R, Yuan H, Emdadi A, Barile E, Chen V, Murphy R, Pellecchia M . 6 . Design, synthesis, and structure-activity relationship of substrate competitive, selective, and in vivo active triazole and thiadiazole inhibitors of the c-Jun N-terminal kinase . Journal of Medicinal Chemistry . 52 . 7 . 1943–52 . April 2009 . 19271755 . 2667321 . 10.1021/jm801503n .
  5. News: AI finds molecules that kill bacteria, but would they make good antibiotics? . 22 March 2023 . Chemical and engineering news (C&EN) . 26 February 2020 . https://web.archive.org/web/20200229191605/https://cen.acs.org/physical-chemistry/computational-chemistry/AI-finds-molecules-kill-bacteria/98/web/2020/02 . 29 February 2020.
  6. Web site: Artificial Intelligence Yields New Antibiotic. 2020-11-13. The MIT Campaign for a Better World. en.
  7. May . Mike . 2023 . How to fight antibiotic resistance . Nature Medicine . 29 . 7 . 1583–1586 . 10.1038/d41591-023-00043-5 . 37464030 . 1078-8956.
  8. Web site: Sample . Ian . vanc . Powerful antibiotic discovered using machine learning for first time . The Guardian . February 20, 2020 .
  9. Stokes JM, Yang K, Swanson K, Jin W, Cubillos-Ruiz A, Donghia NM, MacNair CR, French S, Carfrae LA, Bloom-Ackerman Z, Tran VM, Chiappino-Pepe A, Badran AH, Andrews IW, Chory EJ, Church GM, Brown ED, Jaakkola TS, Barzilay R, Collins JJ . 6 . A Deep Learning Approach to Antibiotic Discovery . Cell . 180 . 4 . 688–702.e13 . February 2020 . 32084340 . 10.1016/j.cell.2020.01.021 . 8349178 . free .
  10. Web site: Artificial intelligence yields new antibiotic . Anne . Trafton . vanc . MIT News Office . February 20, 2020.

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