Discovery of a fluorinated macrobicyclic antibiotic through chemical synthesis

Abstract

The emergence of bacterial antimicrobial resistance threatens to undermine the utility of antibiotic therapy in medicine. This threat can be addressed, in part, by reinventing existing antibiotic classes using chemical synthesis. Here we present the discovery of BT-33, a fluorinated macrobicyclic oxepanoprolinamide antibiotic with broad-spectrum activity against multidrug-resistant bacterial pathogens. Structure–activity relationships within the macrobicyclic substructure reveal structural features that are essential to the enhanced potency of BT-33 as well as its increased metabolic stability relative to its predecessors clindamycin, iboxamycin and cresomycin. Using X-ray crystallography, we determine the structure of BT-33 in complex with the bacterial ribosome revealing that its fluorine atom makes an additional van der Waals contact with nucleobase G2505. Through variable-temperature 1H NMR experiments, density functional theory calculations and vibrational circular dichroism spectroscopy, we compare macrobicyclic homologues of BT-33 and a C7 desmethyl analogue and find that the C7 methyl group of BT-33 rigidifies the macrocyclic ring in a conformation that is highly preorganized for ribosomal binding. Antibiotic resistance can be addressed by reinventing classes of antibiotics through chemical synthesis. Here BT-33—a fully synthetic antibiotic—affords broad-spectrum activity against the bacterial ribosome. X-ray crystallography, theoretical calculations and structure–activity relationship studies reveal the structural features that contribute to the enhanced antibacterial activity and metabolic stability of BT-33.