Discovery of a broad-spectrum, fluorinated macrobicyclic antibiotic through chemical synthesis
Year: 2024
Type: preprint
Abstract: We report the discovery through chemical synthesis of BT-33, a fluorinated macrobicyclic oxepanoprolinamide antibiotic. BT-33 potently inhibits the growth of multidrug-resistant clinical isolates of Gram-positive and Gram-negative bacteria and has an extended half-life in vivo relative to its predecessors cresomycin and iboxamycin. We report structure-activity relationships within the macrobicyclic substructure, which reveal structural features that are essential to the enhanced potency of BT-33 as well as its increased metabolic stability. We determine the structure of BT-33 in complex with the bacterial ribosome by X-ray crystallography, analysis of which suggests that the newly introduced fluorine atom makes an additional Van der Waals contact with nucleobase G2505. Finally, we show that the C7-methyl group of BT-33 rigidifies the macrocyclic ring in a conformation that is highly preorganized for ribosomal binding by using variable-temperature 1H-NMR experiments, density-functional theory calculations, and vibrational circular dichroism spectroscopy to compare macrobicyclic homologs of BT-33 and a C7-desmethyl analog.
Source: ChemRxiv
Authors: Ben Tresco, Kelvin Wu, Antonio Ramkissoon, Elena Aleksandrova, Michael Purdy, Dominic See, Richard Liu, Yury Polikanov, Andrew Myers
Institutions: Harvard University, University of Illinois Chicago
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: National Science Foundation, U.S. Department of Energy, U.S. Department of Health and Human Services, Department of Health and Social Care, Bundesministerium für Bildung und Forschung, Pharmaron, National Institutes of Health, Office of Science, Biomedical Advanced Research and Development Authority, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, Office of Research Infrastructure Programs, National Institutes of Health, Argonne National Laboratory
Awards: G102163711, G107546177, G1313983767, G1383041079, G1664757510, G1993779362, G2061904256, G2070659537, G2287611682, G2398214515, G262962599, G2849897711, G3075337988, G406532759, G409777406, MRI: Acquisition of Single-Crystal Diffractometer for Small Molecule Crystallography and Cryosystem, G4284727806, G4500341707, G498139845, G500928953, G513797252, G5242274761, G5397651101, G5607048534, G6081441115, G6117823089, G6918803902, G78868261, G7970309427, G8344329297, G8500532866, G8656016687, G8783161894, G9000031717, G9000051782, G9000097535, Discovery through chemical synthesis of antibiotics effective against modern bacterial pathogens, G993149817
OpenAlex ID: W4402925707