title: Elucidation of the antimicrobial mechanism of mutacin 1140.
abstract: Mutacin 1140 and nisin A are peptide antibiotics that belong to the lantibiotic family. N-Terminal rings A and B of nisin A and mutacin 1140 (lipid II-binding domain) share many structural and sequence similarities. Nisin A binds lipid II and thus disrupts cell wall synthesis and also forms transmembrane pores. Very little is known about mutacin 1140 in this regard. We performed fluorescence-based studies using a bacteria-mimetic membrane system. The results indicated that lipid II monomers are arranged differently in the mutacin 1140 complex than in the nisin A complex. These differences in complex formation may be attributed to the fact that nisin A uses lipid II to form a distinct pore complex, while mutacin 1140 does not form pores in this membrane system. Further experiments demonstrated that the mutacin 1140-lipid II and nisin A-lipid II complexes are very stable and capable of withstanding competition from each other. Transmembrane electrical potential experiments using a Streptococcus rattus strain, which is sensitive to mutacin 1140, demonstrated that mutacin 1140 does not form pores in this strain even at a concentration 8 times higher than the minimum inhibitory concentration (MIC). Circular complexes of mutacin 1140 and nisin A were observed by electron microscopy, providing direct evidence for a lateral assembly mechanism for these antibiotics. Mutacin 1140 did exhibit a membrane disruptive function in another commonly used artificial bacterial membrane system, and its disruptive activity was enhanced by increasing amounts of anionic phospholipids.
authors.affiliation: Department of Biological Sciences, Mississippi State University, Mississippi State, Mississippi 39762, USA. jls859@msstate.edu
authors.forename: Leif
authors.initials: L
authors.lastname: Smith
authors.forename: Hester
authors.initials: H
authors.lastname: Hasper
authors.forename: Eefjan
authors.initials: E
authors.lastname: Breukink
authors.forename: Jan
authors.initials: J
authors.lastname: Novak
authors.forename: Jirí
authors.initials: J
authors.lastname: Cerkasov
authors.forename: J D
authors.initials: JD
authors.lastname: Hillman
authors.forename: Shawanda
authors.initials: S
authors.lastname: Wilson-Stanford
authors.forename: Ravi S
authors.initials: RS
authors.lastname: Orugunty
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism; D001430:Bacteriocins / Q000737:chemistry* / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D008969:Molecular Sequence Data; D009561:Nisin / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D014538:Uridine Diphosphate N-Acetylmuramic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001430:Bacteriocins; D010455:Peptides; D014538:Uridine Diphosphate N-Acetylmuramic Acid; C069249:muramyl-NAc-(pentapeptide)pyrophosphoryl-undecaprenol; C112560:mutacin 1140; D009561:Nisin; C102526:nisin A