Determining the structure and mode of action of microbisporicin, a potent lantibiotic active against multiresistant pathogens.
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.
Castiglione
Franca
F
Vicuron Pharmaceuticals, Via R. Lepetit 34, 21040 Gerenzano, Varese, Italy.
Lazzarini
Ameriga
A
Carrano
Lucia
L
Corti
Emiliana
E
Ciciliato
Ismaela
I
Gastaldo
Luciano
L
Candiani
Paolo
P
Losi
Daniele
D
Marinelli
Flavia
F
Selva
Enrico
E
Parenti
Francesco
F
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
D000900:Anti-Bacterial Agents; D001430:Bacteriocins; D010455:Peptides; D010457:Peptidoglycan; C528150:microbisporicin; D014364:Tryptophan; D011392:Proline