Introducing BT-33, a Fluorinated Lincosamide Antibiotic

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.

 

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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.

 

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Publikationsverlauf

Artikel online veröffentlicht:
22. Mai 2025