title: Determining the structure and mode of action of microbisporicin, a potent lantibiotic active against multiresistant pathogens.
abstract: Antibiotics blocking bacterial cell wall assembly (beta-lactams and glycopeptides) are facing a challenge from the progressive spread of resistant pathogens. Lantibiotics are promising candidates to alleviate this problem. Microbisporicin, the most potent antibacterial among known comparable lantibiotics, was discovered during a screening applied to uncommon actinomycetes. It is produced by Microbispora sp. as two similarly active and structurally related polypeptides (A1, 2246-Da and A2, 2230-Da) of 24 amino acids linked by 5 intramolecular thioether bridges. Microbisporicin contains two posttranslational modifications that have never been reported previously in lantibiotics: 5-chloro-trypthopan and mono- (in A2) or bis-hydroxylated (in A1) proline. Consistent with screening criteria, microbisporicin selectively blocks peptidoglycan biosynthesis, causing cytoplasmic UDP-linked precursor accumulation. Considering its spectrum of activity and its efficacy in vivo, microbisporicin represents a promising antibiotic to treat emerging infections.
authors.affiliation: Vicuron Pharmaceuticals, Via R. Lepetit 34, 21040 Gerenzano, Varese, Italy.
authors.forename: Franca
authors.initials: F
authors.lastname: Castiglione
authors.forename: Ameriga
authors.initials: A
authors.lastname: Lazzarini
authors.forename: Lucia
authors.initials: L
authors.lastname: Carrano
authors.forename: Emiliana
authors.initials: E
authors.lastname: Corti
authors.forename: Ismaela
authors.initials: I
authors.lastname: Ciciliato
authors.forename: Luciano
authors.initials: L
authors.lastname: Gastaldo
authors.forename: Paolo
authors.initials: P
authors.lastname: Candiani
authors.forename: Daniele
authors.initials: D
authors.lastname: Losi
authors.forename: Flavia
authors.initials: F
authors.lastname: Marinelli
authors.forename: Enrico
authors.initials: E
authors.lastname: Selva
authors.forename: Francesco
authors.initials: F
authors.lastname: Parenti
mesh_terms: D000192:Actinomycetales / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001430:Bacteriocins / Q000737:chemistry / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects* / Q000502:physiology; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D010457:Peptidoglycan / Q000096:biosynthesis; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D014364:Tryptophan / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001430:Bacteriocins; D010455:Peptides; D010457:Peptidoglycan; C528150:microbisporicin; D014364:Tryptophan; D011392:Proline