NMR Study of Mersacidin and Lipid II Interaction in Dodecylphosphocholine Micelles

Hsu, Shang-Te Danny; Breukink, Eefjan; Bierbaum, Gabriele; Sahl, Hans‐Georg; Kruijff, Ben de; Kaptein, R.; Nuland, Nico A. J. van; Bonvin, Alexandre M. J. J.

doi:10.1074/jbc.m211144200

Cited by 125 publications

(121 citation statements)

References 49 publications

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“…Mersacidin forms a tightly associated 1:1 complex with Lipid II, and nisin sequesters Lipid II via encapsulating the pyrophosphate of Lipid II within a hydrogen bond network formed by nisin backbone amides (36,37). The nisin-Lipid II complex organizes into a supramolecular pore-like assembly, engendering a breach in membrane integrity and leading to cell death by osmotic lysis (38)(39)(40).…”

Section: Discussionmentioning

confidence: 99%

A crystal structure of a dimer of the antibiotic ramoplanin illustrates membrane positioning and a potential Lipid II docking interface

Hamburger

Hoertz

Lee

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The glycodepsipeptide antibiotic ramoplanin A2 is in late stage clinical development for the treatment of infections from Grampositive pathogens, especially those that are resistant to first line antibiotics such as vancomycin. Ramoplanin A2 achieves its antibacterial effects by interfering with production of the bacterial cell wall; it indirectly inhibits the transglycosylases responsible for peptidoglycan biosynthesis by sequestering their Lipid II substrate. Lipid II recognition and sequestration occur at the interface between the extracellular environment and the bacterial membrane. Therefore, we determined the structure of ramoplanin A2 in an amphipathic environment, using detergents as membrane mimetics, to provide the most physiologically relevant structural context for mechanistic and pharmacological studies. We report here the X-ray crystal structure of ramoplanin A2 at a resolution of 1.4 Å. This structure reveals that ramoplanin A2 forms an intimate and highly amphipathic dimer and illustrates the potential means by which it interacts with bacterial target membranes. The structure also suggests a mechanism by which ramoplanin A2 recognizes its Lipid II ligand.glycolipodepsipeptide ͉ mechanism ͉ vancomycin resistance

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Section: Discussionmentioning

confidence: 99%

A crystal structure of a dimer of the antibiotic ramoplanin illustrates membrane positioning and a potential Lipid II docking interface

Hamburger

Hoertz

Lee

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…1) (17,18,29,30). Importantly, the six-aminoacid-containing MeLan B-ring in Hal␣, which is believed to be important for lipid II binding in mersacidin's C-ring (32), is conserved including the invariant and essential Glu within this ring (33). This MeLan ring is also found in the ␣͞A1-peptides of lacticin 3147 (21), plantaricin W (17), staphylococcin C55 (18), Smb (29), and BHT-A (30), as well as in the A-ring of the lacticin 481 subgroup of single component lantibiotics (3).…”

Section: Discussionmentioning

confidence: 99%

Discovery and in vitro biosynthesis of haloduracin, a two-component lantibiotic

McClerren¹,

Cooper

Quan

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

234

321

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Lantibiotics are ribosomally synthesized peptides that undergo posttranslational modifications to their mature, antimicrobial form. They are characterized by the unique amino acids lanthionine and methyllanthionine, introduced by means of dehydration of Ser͞Thr residues followed by reaction of the resulting dehydro amino acids with cysteines to form thioether linkages. Two-component lantibiotics use two peptides that are each posttranslationally modified to yield two functionally distinct products that act in synergy to provide bactericidal activity. By using genetic data instead of isolation, a two-component lantibiotic, haloduracin, was identified in the genome of the Gram-positive alkaliphilic bacterium Bacillus halodurans C-125. We show that heterologously expressed and purified precursor peptides HalA1 and HalA2 are processed by the purified modification enzymes HalM1 and HalM2 in an in vitro reconstitution of the biosynthesis of a two-component lantibiotic. The activity of each HalM enzyme is substratespecific, and the assay products exhibit antimicrobial activity after removal of their leader sequences at an engineered Factor Xa cleavage site, indicating that correct thioether formation has occurred. Haloduracin's biological activity depends on the presence of both modified peptides. The structures of the two mature haloduracin peptides Hal␣ and Hal␤ were investigated, indicating that they have similarities as well as some distinct differences compared with other two-component lantibiotics.lanthionine ͉ dehydroalanine ͉ antibiotic

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“…Considering the mode of action of lantibiotics, this speculation seems to be reasonable. It has been shown that several lantibiotics, including nisin (11,14), LtnAI (␣-peptide of lacticin 3147) (38), and mersacidin (3,13), use lipid II, a cell wall precursor located on the membrane, as a docking molecule. After docking, these lantibiotics form pores on the cytoplasmic membrane and/or inhibit cell wall biosynthesis.…”

Section: Discussionmentioning

confidence: 99%

Functional Significance of the E Loop, a Novel Motif Conserved in the Lantibiotic Immunity ATP-Binding Cassette Transport Systems

Okuda¹,

Yanagihara²,

Sugayama³

et al. 2010

J Bacteriol

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Lantibiotics are peptide-derived antibacterial substances produced by some Gram-positive bacteria and characterized by the presence of unusual amino acids, like lanthionines and dehydrated amino acids. Because lantibiotic producers may be attacked by self-produced lantibiotics, they express immunity proteins on the cytoplasmic membrane. An ATP-binding cassette (ABC) transport system mediated by the LanFEG protein complex is a major system in lantibiotic immunity. Multiple-sequence alignment analysis revealed that LanF proteins contain the E loop, a variant of the Q loop, which is a well-conserved motif in the nucleotide-binding domains (NBDs) of general ABC transporters. To elucidate E loop function, we introduced a mutation in the NukF protein, which is involved in the nukacin-ISK-1 immunity system. Amino acid replacement of glutamic acid in the E loop with glutamine (E85Q) resulted in slight decreases in the immunity level and transport activity. Additionally, the E85A mutation severely impaired the immunity level and transport activity. On the other hand, ATPase activities of purified E85Q and E85A mutants were almost similar to that of the wild type. These results suggested that the E loop found in ABC transporters involved in lantibiotic immunity plays a significant role in the function of these transporters, especially in the structural change of transmembrane domains.

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NMR Study of Mersacidin and Lipid II Interaction in Dodecylphosphocholine Micelles

Abstract: Mersacidin belongs to the type B lantibiotics (lanthi-onine

Cited by 125 publications

References 49 publications

A crystal structure of a dimer of the antibiotic ramoplanin illustrates membrane positioning and a potential Lipid II docking interface

A crystal structure of a dimer of the antibiotic ramoplanin illustrates membrane positioning and a potential Lipid II docking interface

Discovery and in vitro biosynthesis of haloduracin, a two-component lantibiotic

Functional Significance of the E Loop, a Novel Motif Conserved in the Lantibiotic Immunity ATP-Binding Cassette Transport Systems

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