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: Franca Castiglione, Ameriga Lazzarini, Lucia Carrano, Emiliana Corti, Ismaela Ciciliato, Luciano Gastaldo, Paolo Candiani, Daniele Losi, Flavia Marinelli, Enrico Selva, Francesco Parenti
• Journal: Chemistry & biology (Chem Biol) Vol. 15 Issue 1 Pg. 22-31 (Jan 2008) ISSN: 1074-5521 [Print] United States
• PMID: 18215770 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Bacteriocins
• Peptides
• Peptidoglycan
• microbisporicin
• Tryptophan
• Proline

Topics

• Actinomycetales (chemistry, drug effects, metabolism)
• Amino Acid Sequence
• Anti-Bacterial Agents (chemistry, pharmacology)
• Bacteriocins (chemistry, pharmacology)
• Drug Resistance, Multiple, Bacterial (drug effects, physiology)
• Molecular Sequence Data
• Peptides (chemistry, pharmacology)
• Peptidoglycan (biosynthesis)
• Proline (analogs & derivatives, pharmacology)
• Tryptophan (analogs & derivatives, pharmacology)