Isolation and characterization of epilancin 15X, a novel lantibiotic from a
clinical strain of Staphylococcus epidermidis

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Information obtained from PDB's Chemical Component Dictionary
at http://wwpdb-remediation.rutgers.edu/downloads.html
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Information obtained from PDB's Chemical Component Dictionary
at http://wwpdb-remediation.rutgers.edu/downloads.html
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4-[({4-[(1R,2S,4S)-2-hydroxy-4-phenylcyclohexyl]phenyl}carbonyl)amino]butanoic acid

4-[[4-[(1R,2S,4S)-2-hydroxy-4-phenyl-cyclohexyl]phenyl]carbonylamino]butanoic acid

Isolation and structural characterization of epilancin 15X, a novel lantibiotic from a clinical strain of Staphylococcus epidermidis.

Nisin is an example of type-A lantibiotics that contain cyclic lanthionine rings
and unusual dehydrated amino acids. Among the numerous pore-forming
antimicrobial peptides, type-A lantibiotics form an unique family of
post-translationally modified peptides. Via the recognition of cell wall
precursor lipid II, nisin has the capacity to form pores against Gram-positive
bacteria with an extremely high activity in the nanomolar (nM) range. Here we
report a high-resolution NMR spectroscopy study of nisin/lipid II interactions
in SDS micelles as a model membrane system in order to elucidate the mechanism
of molecular recognition at residue level. The binding to lipid II was studied
through (15)N-(1)H HSQC titration, backbone amide proton temperature
coefficient analysis, and heteronuclear (15)N[(1)H]-NOE relaxation dynamics
experiments. Upon the addition of lipid II, significant changes were monitored
in the N-terminal part of nisin. An extremely low amide proton temperature
coefficient (Delta delta/Delta T) was found for the amide proton of Ala3 (>
-0.1 ppb/K) in the complex form. This suggests tight hydrogen bonding and/or
isolation from the bulk solvent for this residue. Large chemical shift
perturbations were also observed in the first two rings. In contrast, the
C-terminal part of nisin was almost unaffected. This part of the molecule
remains flexible and solvent-exposed. On the basis of our results, a multistep
pore-forming mechanism is proposed. The N-terminal part of nisin first binds to
lipid II, and a subsequent structural rearrangement takes place. The C-terminal
part of nisin is possibly responsible for the activation of the pore formation.
In light of the emerging antibiotic resistance problems, an understanding of
the specific recognition mechanism of nisin with lipid II at the residue
specific level may therefore aid in the development of novel antibiotics.

Hsu ST, Breukink E, de Kruijff B, Kaptein R, Bonvin AM, van Nuland NA.
Mapping the targeted membrane pore formation mechanism by solution NMR:
the nisin Z and lipid II interaction in SDS micelles.
Biochemistry. 2002 Jun 18;41(24):7670-6.

Mapping the targeted membrane pore formation mechanism by solution NMR: the nisin Z and lipid II interaction in SDS micelles.

Mersacidin belongs to the type B lantibiotics (lanthionine-containing
antibiotics) that contain post-translationally modified amino acids and cyclic
ring structures. It targets the cell wall precursor lipid II and thereby
inhibits cell wall synthesis. In light of the emerging antibiotics resistance
problem, the understanding of the antibacterial activity on a structural basis
provides a key to circumvent this issue. Here we present solution NMR studies
of mersacidin-lipid II interaction in dodecylphosphocholine (DPC) micelles.
Distinct solution structures of mersacidin were determined in three different
states: in water/methanol solution and in DPC micelles with and without lipid
II. The structures in various sample conditions reveal remarkable
conformational changes in which the junction between Ala-12 and Abu-13 (where
Abu is aminobutyric acid) effectively serves as the hinge for the opening and
closure of the ring structures. The DPC micelle-bound form resembles the
previously determined NMR and x-ray crystal structures of mersacidin in pure
methanol but substantially deviates from the other two states in our current
report. The structural changes delineate the large chemical shift perturbations
observed during the course of a two-step (15)N-(1)H heteronuclear single
quantum coherence titration. They also modulate the surface charge distribution
of mersacidin suggesting that electrostatics play a central role in the
mersacidin-lipid II interaction. The observed conformational adaptability of
mersacidin might be a general feature of lipid II-interacting
antibiotics/peptides.

Hsu ST, Breukink E, Bierbaum G, Sahl HG, de Kruijff B, Kaptein R, van Nuland
NA, Bonvin AM.
Free Full Text NMR study of mersacidin and lipid II interaction in
dodecylphosphocholine micelles. Conformational changes are a key to
antimicrobial activity.
J Biol Chem. 2003 Apr 11;278(15):13110-7. Epub 2003 Jan 31.

NMR study of mersacidin and lipid II interaction in dodecylphosphocholine micelles. Conformational changes are a key to antimicrobial activity.

The emerging antibiotics-resistance problem has underlined the urgent need for
novel antimicrobial agents. Lantibiotics (lanthionine-containing antibiotics)
are promising candidates to alleviate this problem. Nisin, a member of this
family, has a unique pore-forming activity against bacteria. It binds to lipid
II, the essential precursor of cell wall synthesis. As a result, the membrane
permeabilization activity of nisin is increased by three orders of magnitude.
Here we report the solution structure of the complex of nisin and lipid II. The
structure shows a novel lipid II-binding motif in which the pyrophosphate
moiety of lipid II is primarily coordinated by the N-terminal backbone amides
of nisin via intermolecular hydrogen bonds. This cage structure provides a
rationale for the conservation of the lanthionine rings among several lipid
II-binding lantibiotics. The structure of the pyrophosphate cage offers a
template for structure-based design of novel antibiotics.

Hsu ST, Breukink E, Tischenko E, Lutters MA, De Kruijff B, Kaptein R, Bonvin
AM, Van Nuland NA.
The nisin-lipid II complex reveals a pyrophosphate cage that provides a
blueprint for novel antibiotics.
Nat Struct Mol Biol. 2004 Oct;11(10):963-7. Epub 2004 Sep 12.

The nisin-lipid II complex reveals a pyrophosphate cage that provides a blueprint for novel antibiotics.

A Chain A, Isolation And Characterization OfEpilancin 15x, A Novel Antibiotic From A ClinicalStrain Of Staphylococcus Ep