Tresco BIC,
Wu KJY,
Ramkissoon A,
Aleksandrova EV,
Purdy M,
See DNY,
Liu RY *,
Polikanov YS *,
Myers AG *.
Harvard University, Cambridge and University of Illinois at Chicago, USA
Discovery of a Fluorinated Macrobicyclic Antibiotic through Chemical Synthesis.
Nat. Chem. 2025;
17: 582-589
DOI:
10.1038/s41557-025-01738-7
Keywords
antibiotic - lincosamide - fluorine
Significance
The lincosamides are a class of ribosome-binding antibiotics based on the natural
product lincomycin. Like all antibiotics, this class of compounds is becoming less
effective with the emergence of bacterial resistance, necessitating the development
of new, semisynthetic derivatives. The Myers lab has previously shown that the oxepanoprolinamide-containing
derivatives (e. g., IBX) can bypass lincosamide-resistance in bacteria and that rigidification of the sulfur
atom in a 10-membered ring (e. g., CRM) improves efficacy against both Gram-positive and Gram-negative bacteria. Herein,
they report a new derivative, BT-33, which displays enhanced potency and increased metabolic stability relative to its
predecessors.
Comment
BT-33 was accessed in 17 synthetic steps from d-galactose (or in 12 steps from a known compound). The fluorine atom is introduced
in a ring-expansion reaction of the primary alcohol. X-ray crystallography revealed
the fluorine atom increases the binding affinity of the molecule for the bacterial
ribosome via van der Waals interactions. In addition to increased potency, the 11-membered
fluoro-containing ring conferred improved metabolic stability on the antibiotic.
