title: The antibiotic Furvina® targets the P-site of 30S ribosomal subunits and inhibits translation initiation displaying start codon bias.
abstract: Furvina®, also denominated G1 (MW 297), is a synthetic nitrovinylfuran [2-bromo-5-(2-bromo-2-nitrovinyl)-furan] antibiotic with a broad antimicrobial spectrum. An ointment (Dermofural®) containing G1 as the only active principle is currently marketed in Cuba and successfully used to treat dermatological infections. Here we describe the molecular target and mechanism of action of G1 in bacteria and demonstrate that in vivo G1 preferentially inhibits protein synthesis over RNA, DNA and cell wall synthesis. Furthermore, we demonstrate that G1 targets the small ribosomal subunit, binds at or near the P-decoding site and inhibits its function interfering with the ribosomal binding of fMet-tRNA during 30S initiation complex (IC) formation ultimately inhibiting translation. Notably, this G1 inhibition displays a bias for the nature (purine vs. pyrimidine) of the 3'-base of the codon, occurring efficiently only when the mRNA directing 30S IC formation and translation contains the canonical AUG initiation triplet or the rarely found AUA triplet, but hardly occurs when the mRNA start codon is either one of the non-canonical triplets AUU or AUC. This codon discrimination by G1 is reminiscent, though of opposite type of that displayed by IF3 in its fidelity function, and remarkably does not occur in the absence of this factor.
authors.affiliation: Laboratory of Genetics, Department of Biosciences & Biotechnology, University of Camerino, 62032 Camerino, MC, Italy. attilio.fabbretti@unicam.it
authors.forename: Attilio
authors.initials: A
authors.lastname: Fabbretti
authors.forename: Letizia
authors.initials: L
authors.lastname: Brandi
authors.forename: Dezemona
authors.initials: D
authors.lastname: Petrelli
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Pon
authors.forename: Nilo R
authors.initials: NR
authors.lastname: Castañedo
authors.forename: Ricardo
authors.initials: R
authors.lastname: Medina
authors.forename: Claudio O
authors.initials: CO
authors.lastname: Gualerzi
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001665:Binding Sites; D018387:Codon, Initiator; D005663:Furans / Q000494:pharmacology*; D010442:Peptide Chain Initiation, Translational / Q000187:drug effects*; D054680:Ribosome Subunits, Small, Bacterial / Q000737:chemistry / Q000187:drug effects*; D014753:Vinyl Compounds / Q000494:pharmacology*
chemical_list: C577632:2-bromo-5-(2-bromo-2-nitrovinyl)furan; D000900:Anti-Bacterial Agents; D018387:Codon, Initiator; D005663:Furans; D014753:Vinyl Compounds