Adding Fluorine Helps Ailing Antibiotic

A strategically placed fluorine today could keep antibiotic resistance at bay. Aminoglycosides are a class of antibiotics that have traditionally been useful against infections in patients with severe burns or cystic fibrosis. Antibiotic-resistant bacteria have emerged, however, carrying an arsenal of aminoglycoside-inactivating enzymes. One approach to counter the enzymes has been to remove certain aminoglycoside hydroxyl groups. But that change can make the drugs toxic to the kidneys. Stephen Hanessian and colleagues at the University of Montreal instead tinkered with neomycin B, an aminoglycoside and the active ingredient in popular over-the-counter antibiotic ointments, to see whether fluorination might help. When Hanessian’s team replaced the 4´-hydroxyl group on neomycin’s A-ring with an axial fluorine (shown), they created an analog that evades aminoglycoside-inactivating enzymes in bacterial cell cultures (Chem. Sci. 2014, DOI: 10.1039/c4sc01626b). Adding an (S)-hydroxyaminobutyric acid to neomycin’s B-ring and fluorinating it was also effective (ACS Chem. Biol. 2014, DOI: 10.1021/cb5003416). To see how fluorine made a difference, Hanessian’s team used X-ray crystallography. Aminoglycosides interfere with bacterial protein synthesis by binding tightly to a microbe’s ribosomal RNA in a position called the A-site. The crystal structure shows that axial fluorine contacts a guanine nucleic acid in the A-site.