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Antibiotic Action and Peptidoglycan Formation on Tethered Lipid Bilayer Membranes.

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Angewandte
Chemie
Lipid Bilayers
DOI: 10.1002/ange.200504035
Antibiotic Action and Peptidoglycan Formation
on Tethered Lipid Bilayer Membranes**
Michael J. Spencelayh, Yaling Cheng, Richard J. Bushby,
Timothy D. H. Bugg, Jian-jun Li, Peter J. F. Henderson,
John O%Reilly, and Stephen D. Evans*
The inner-bilayer membranes of Gram-positive bacteria are
surrounded by a layer of peptidoglycan, in the form of a
polymer net, which serves to provide mechanical support
against lysis due to osmotic stress. Prevention of peptidoglycan formation makes bacterial cells prone to lysis and
represents one of the three main mechanisms of antibiotic
action; the others being inhibition of protein synthesis and the
inhibition of RNA/DNA synthesis.[1] Vancomycin has been a
mainstay of the glycopeptide antibiotics and is active against a
wide range of Gram-positive bacteria. However, the emergence of widespread resistance amongst pathogenic bacteria
has highlighted the need for new and effective antibacterial
compounds, and consequently there has been a significant
effort devoted to understanding the mechanisms of antibiotic
action and resistance.[2a–e]
Most studies performed, to date, on understanding the
structure–function relationship involved in antibiotic interaction with peptidoglycan precursors have focused on the use
of micelles, vesicles, and soluble precursors. Although important information has been gained from such studies, there are
drawbacks in that either they do not represent a close mimic
of the in vivo situation or, in the case of vesicles, they are not
amenable to study by using the array of surface-science
techniques currently available. In 1997, Williams et al. formed
[*] Prof. S. D. Evans
School of Physics and Astronomy
University of Leeds
Leeds, LS2 9JT (United Kingdom)
Fax: (+ 44) 113-343-1884
E-mail: s.d.evans@leeds.ac.uk
Prof. P. J. F. Henderson, Dr. J. O’Reilly
Astbury Centre for Structural Molecular Biology
University of Leeds
Leeds, LS2 9JT (UK)
Dr. M. J. Spencelayh, Dr. Y. Cheng, Prof. R. J. Bushby
Centre for Self-Organising Molecular systems
University of Leeds
Leeds, LS2 9JT (UK)
Prof. T. D. H. Bugg, Dr. J.-j. Li
Department of Chemistry
University of Warwick
Coventry, CV4 7AL (UK)
[**] The authors would like to thank GlaxoSmithKline (PA, USA) for
funding this work. Ramoplanin was provided by Dr. S. Donadio
(Vicuron Pharmaceuticals).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. 2006, 118, 2165 –2170
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Zuschriften
a “hybrid” bilayer that consisted of a lipid
monolayer adsorbed onto a hydrophobic
self-assembled monolayer (SAM).[3a] The
lipid monolayer was decorated with N-aDocosanoyl-e-acetyl Lys d-Ala d-Ala
(Doc-KAA) and was shown to bind vancomycin and other glycopeptide antibiotics. The dissociation constant for vancomycin was determined to be 0.7 mm. In a
subsequent study in which the terminal dAla residue was replaced by a d-lactate
residue, the degree of binding was reduced
significantly, yielding a Kd value of
1000 mm.[3b]
Solid-supported bilayer lipid membranes (sBLMs) and tethered-bilayer lipid
membranes (tBLMs) have been used
widely in recent years for the investigation
of ion-channel proteins and the development of biosensors.[4a–f] These bilayers are
fluid and represent a reasonable mimic, for
Figure 1. Schematic diagram showing the principal stages involved in in vivo cell-wall
many purposes, of the cell membrane.[4e,f]
biosynthesis. UMP = uridine-5’monophosphate.
Herein, we show that tBLMs can
provide a suitable platform for addressing
questions related to antibiotic resistance.
We started by introducing two precursors to peptidoglycan
formation—namely, the full-length “native” versions of lipid I
and lipid II. The incorporation of functional lipid I or lipid II
is demonstrated by specific binding of vancomycin and
ramoplanin. In a further step, we showed that native E. coli
membranes can be used to form tBLMs (and sBLMs) and that
these contain the necessary functional proteins for the in vitro
synthesis of the peptidoglycan cell wall. This system possibly
represents the closest mimic of the in vivo situation yet.
Figure 1 shows the major steps involved in in vivo cellwall biosynthesis. Soluble UDP MurNAc pentapeptide
(UDP = undecaprenyl phosphate, MurNAc = N-acetylmuramic acid) is localized at the membrane surface by the
MraY enzyme and attached to the lipid carrier UDP. The
resulting “lipid I” molecule is modified by the enzyme MurG,
with the addition of UDP GlcNAc (GlcNAc = N-acetylglucosamine), forming the “lipid II” molecule. Lipid II “flips”
from the cytoplasm to the outside of the cell, where it is crosslinked, by the transglycosylase and transpeptidase enzymes,
to form the peptidoglycan cell wall. The undecaprenyl lipid
carrier is then recycled.[5, 6a,b, 7] The glycopeptide antibiotic,
vancomycin, and the lipodepsipeptide antibiotic, ramoplanin,
are believed to inhibit peptidoglycan biosynthesis by complexation with the peptidoglycan precursor (lipid II).[2a, 5, 6a,b, 8]
Vancomycin prevents transglycosylation by binding to the Cterminal d-Ala d-Ala groups. The emergence of vancomycin
resistance, due to mutation of the terminal d-Ala d-Ala
group to d-Ala d-lactate has highlighted a need for alterFigure 2. A) Schematic diagram showing the binding of glycopeptide
native antibiotics.[1] Ramoplanin is a potential candidate, as it
antibiotics to cell-wall precursors in a tethered bilayer containing lipids
has been shown to inhibit the transglycosylasation step by
I or II. B) Vancomycin binding to tethered bilayers containing lipid I.
binding to the MurNAc l-Ala portion of lipid II, that is, close
The Figure shows the increase in adsorbed-layer thickness, Dd, as a
[9a–f]
to the membrane interface.
function of antibiotic concentration, determined using SPR. C) VancoThe tethered lipid bilayers (Figure 2 A) were formed by
mycin binding to tethered bilayers containing lipid II. Error bars
immersing a “mixed”, cholesteryl containing, self-assembledindicate the deviation observed between multiple experiments.
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2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. 2006, 118, 2165 –2170
Angewandte
Chemie
monolayer (SAM) modified support into a solution containing egg-phosphatidylcholine (PC) vesicles.[4b] The vesicles
contained lipid I or lipid II (20 % by weight). Bilayer formation was traced by using surface plasmon resonance (SPR)
and impedance spectroscopy. The fully formed bilayers gave
capacitance values of 0.69 mF cm 2, which is consistent with
the determined thickness (from SPR) and indicates the
formation of continuous bilayers with few defects.
The binding of vancomycin to lipid I (and lipid II) was
measured through the incubation of the bilayers with
solutions containing increasing concentrations of antibiotic.
The amount of adsorbed material was determined by using
SPR and plotted against the vancomycin concentration
(Figure 2 B, C). The data presented were corrected for
nonspecific binding by subtraction of the change in thickness
observed in the control experiments from that of pure egg-PC
bilayers, that is, with no lipid I (or II) present, and tested over
the same range of antibiotic concentrations. In all cases, the
degree of nonspecific binding was less than 20 % of that
observed in the presence of lipid I (or II). The data were fitted
by using the Hill equation to obtain estimates of the Hill
coefficient, nH, and the dissociation constant Kd (Table 1). The
Figure 3 A shows a real-time SPR trace that tracks the
binding of ramoplanin to a bilayer, incorporating lipid I, over
a range of antibiotic concentrations. Figure 3 B and C show
the change in adsorbed layer thickness, as a function of
Table 1: Equilibrium dissociation constants and Hill coefficients
obtained from fits to the binding data in Figures 2 and 3.
Bilayer/Antibiotic
nH[a]
Kd [mM][b]
lipid I/vancomycin
lipid II/vancomycin
lipid I/ramoplanin
lipid II/ramoplanin
1.7 0.3
3.5 0.1
1.3 0.1
2.1 0.5
91 8
59 0.5
7.8 0.4
1.6 0.2
[a] nH = Hill coefficient [b] Kd = dissociation constant.
Hill coefficient relates to the degree of cooperativity in the
binding event, with nH < 1 indicating negative cooperativity
and nH > 1 indicating positive cooperativity. In both cases, we
found that nH > 1 (for lipid I and lipid II), suggesting that the
binding of vancomycin to lipid II (or I) lowers the energy
barrier for the binding of a subsequent vancomycin molecule
(or dimer). Our results also indicate that vancomycin binding
to lipid II is stronger (lower Kd) and has a greater degree of
cooperativity (higher nH) than to lipid I. The difference in Kd
values (for lipid I and lipid II) implies that interactions
between the precursor and sugar groups, attached to the
peptide backbone of vancomycin, may also influence the
nature of the interaction.[10a,b] It should be noted, however,
that the Kd values for vancomycin are approximately an order
of magnitude larger than those for the surface-bound peptide
(KAA) analogues.[3a–d] To our knowledge, there has only been
one study of vancomycin binding to lipid II, by Vollmerhaus
and co-workers, in which a water soluble lipid II analogue was
compared to the more widely studied KAA model peptide.[3e]
The dissociation constant for the lipid II analogue was less
than half that for the model peptide and similair to those
reported by Williams, Whitesides, and co-workers.[3a–d]
Although the absolute values determined from our systems
do differ, the observed trends are similar despite that our
systems are different (using native precursors embedded in a
lipid bilayer).
Angew. Chem. 2006, 118, 2165 –2170
Figure 3. A) SPR measurements showing ramoplanin binding (change
in thickness; Dd) to a tethered bilayer containing lipid I as a function
of time. The vertical dashed lines indicate points at which the
concentration of the antibiotic was increased. B) Change in thickness,
Dd, of the adsorbed layer on a bilayer containing lipid I as a function
of ramoplanin concentration. C) Change in thickness, Dd, of the
adsorbed layer on a bilayer containing lipid II as a function of
ramoplanin concentration. Error bars indicate the standard deviation
observed between multiple experiments; note that experiments on
lipid II containing bilayers were not repeated due to limited stocks of
ramoplanin. Ram = ramoplanin.
ramoplanin concentration, upon incubation with bilayers that
contain lipid I and lipid II, respectively. These data fits give
Hill coefficients greater than one, suggesting the presence of a
cooperative phenomenon. Further, the value of nH for binding
to lipid II is nearly twice that of lipid I, whereas the
dissociation constant is approximately four-times smaller
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Zuschriften
Figure 5 A shows an SPR trace showing the change in
(Table 1). Walker, McCafferty, and co-workers have indeaverage thickness during peptidoglycan biosynthesis onto a
pendently shown that ramoplanin undergoes aggregation
preformed E. coli tBLM. At t = 0, the soluble precursors
resulting in formation of insoluble fibrils in the presence of
UDP MurNAc pentapeptide and UDP GlcNAc (each at a
the soluble analogues of lipid I and II.[9a–f] The detailed
1
H NMR spectroscopy studies performed by Walker,
McCafferty, and co-workers provided a major advance in
the identification of the binding interface and provided
estimates of the dissociation constants for the soluble
precursors citronellyl–lipid I (Kd < 100 mm)[9d] and citronellyl–lipid II (Kd 50 nm).[9c] More recently, Walker
and co-workers have reported that ramoplanin binds to
analogues of lipid II between five and ten-times more
strongly than to analogues of lipid I.[9g] As ramoplanin
binding involves the MurNAc GlcNAc moiety of lipid II, which resides close to the membrane interface, one
might expect steric effects to affect the magnitude of the
Kd values observed in our studies (compared to those
found by using the water-soluble analogues cited above).
Notwithstanding this, it is clear that our membrane
consists of “native” peptidoglycan precursors that
behave in a qualitatively similar manner to those
reported by Walker and co-workers, and supports the
notion that lipid II is the primary target (and that
Figure 5. SPR kinetics traces showing changes in adsorbed film thickness,
Dd, as a function of time. Trace A shows the formation of a peptidoglycan
inhibition of the transglycosylase step is the primary
layer on a tethered E. coli membrane. Traces B–E show the results obtained
mode of antibacterial action).[9g]
in a number of control experiments (offset for clarity). Trace B shows the
The native E. coli inner membrane contains the full
absence of ATP/Mg2+, and Trace C shows the absence of UDP GlcNAc.
range of intrinsic and extrinsic proteins necessary for
Trace D shows the absence of both UDP GlcNAc and UDP MurNAc
bacterial cell-wall formation. Vesicles of this membrane,
pentapeptide; and in trace E, the conditions are as for trace A except that
created by using the French-press technique, were used
the bilayer is formed from pure egg-PC vesicles. Inset: shows bilayer
formation, followed by an attempt at peptidoglycan biosynthesis after the
to form sBLMs and tBLMs of the native inner memintroduction of Vancomycin (VAN; 5 mm).
brane. Figure 4 shows the kinetics of bilayer formation,
as determined from SPR, and indicates that the bilayers
are formed within 20 min and are stable to rinsing with
buffer solution (see Experimental Section). The average
concentration of 0.05 mg mL 1) were introduced to the baththickness of the adsorbed lipid film was 3.8 0.2 nm
ing solution. The resulting increase in thickness can be
(obtained from fitting the “before” and “after” curves
attributed to the attachment, modification, and cross-linking
shown in the inset). If one takes into account the insertion
of the pentapeptide to form a peptidoglycan cell wall.[6b, 7]
of anchor groups into the lower leaflet of the membrane, we
In vivo, the first steps of peptidoglycan formation occur on
would expect a thickness change of 3.6 nm (taking the E. coli
the inner leaflet of the membrane before “flipping” to the
membrane thickness to be 4.5 nm),[11] that is, close to that
outer leaflet for the later stages. It is likely that the in vivo
bacterial inner-membrane proteins are arranged asymmetrifound experimentally.
cally in the bilayer. The French-press method of vesicle
preparation used herein forms both the inside-out and rightside-out vesicles. As a result, the “flipping” stage is not
required for peptidoglycan synthesis on a tethered-membrane
bilayer. The average thickness of the cell wall was 1.6 0.2 nm. After a rinsing with clean buffer solution to remove
any adventitiously bound material, this value fell to 1.1 0.1 nm. The thickness of a fully formed E. coli cell wall
in vivo is typically close to 3 nm, thus our data correspond to
about 35 % of a full peptidoglycan layer.[11] This compares
favorably to previously reported values of in vitro cell-wall
biosyntheses (measured in vesicles by the incorporation of
radiolabeled precursors), which achieved 2 % of the in vivo
level.[6b] Traces 5 B–E show a number of control experiments
that were designed to test the hypothesis outlined above.
Figure 4. SPR trace showing the kinetics of adsorption (change in
Trace 5 B shows the same experiment as that of trace 5 A, but
thickness, Dd, versus time). Insert: SPR curves showing the angular
in the absence of adenosinetriphosphate (ATP) and MgCl2.
shift in the reflectance, R, minimum following adsorption of a 3.5-nm
ATP is required for the recycling of UDP molecules and Mg2+
tethered proteolipid layer on a mixed SAM.
2168
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2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. 2006, 118, 2165 –2170
Angewandte
Chemie
ions that are cofactors for the proteins of cell-wall biosynthesis. In this experiment, no increase in thickness was
observed, indicating the necessity for recycling of UDP to
create sufficient quantities of lipid I in the bilayer. In the case
of trace 5 C, the UDP GlcNAc molecule is missing from the
experiment, and as a result, cell-wall biosynthesis can only
proceed as far as the attachment of UDP MurNAc pentapeptide to the surface. Although lipid I to lipid II modification cannot occur as there is no substrate for the enzyme, a
small change in thickness is observed 0.1 nm. This is
possibly attributable to the localization of unmodified pentapeptide at the surface and is within the uncertainty of our
measurements. The fourth trace, 5 D, shows an experiment
wherein both UDP -MurNAc pentapeptide and UDP
GlcNAc were omitted. The bilayer was rinsed with buffer
solution containing only ATP and MgCl2, and resulted in no
increase in the thickness of the lipid layer. Trace 5 E was
obtained under the same conditions as trace 5 A except that a
pure egg-PC bilayer was used rather than the E. coli inner
membrane. Once again, there was no evidence of any cell-wall
biosynthesis. Finally, cell-wall biosynthesis was attempted in
the presence of 5 mm Vancomycin, a glycopeptide antibiotic
that disrupts cell walls by binding to lipid-linked precursors
prior to transglycosylation.[2a–e] The resulting adsorbed film
(see the inset in Figure 5) was readily removed by a single
rinse with clean buffer solution, suggesting (at best) the
formation of a weakened cell wall in the presence of the
antibiotic.
These controls demonstrate that the increase in thickness
observed requires; 1) the presence of both soluble cell-wall
precursors (lipid I and II), 2) the presence of ATP and Mg2+,
3) the use E. coli inner membranes, and 4) that it can be
disrupted by glycopeptide antibiotics. These data strongly
suggest that protein-mediated peptidoglycan cell-wall biosynthesis is occurring at the membrane surface, demonstrating that the proteins involved in bacterial cell-wall synthesis
have been maintained in a functional form.
Herein we describe the first demonstration of a tethered
bacterial membrane that is capable of the biosynthesis of a
peptidoglycan cell wall. This system readily lends itself to a
range of applications including the search for novel antibiotics
and fundamental studies of cell-wall formation, for example,
it is not known whether ramoplanin–lipid II complexes
polymerize in the membrane as they do in solution. The
planar nature of the tBLMs not only allows investigation with
a wide range of analytical techniques, but also is compatible
with array formation for high-throughput screening of novel
bactericidal agents.
Experimental Section
The mixed SAMs were comprised of “anchor” molecules (HS(CH2CH2O)5 CH2CH2NHCHO2-Cholesteryl) that were 50 % by mole
fraction on the surface and were designed to tether the lipid bilayer to
the solid support. “Spacer” molecules (HS(CH2)2OH) were used to
promote a hydrophilic region beneath the lipid bilayer. These SAMs
were fully characterised by using X-ray photoelectron spectroscopy
(XPS), wetting, and Ellipsometry.
The synthesis of lipids I and II was carried out according to the
method of Brandish et al. with the exception that they were extracted
Angew. Chem. 2006, 118, 2165 –2170
by using 1-butanol.[12] E. coli strain JM1100 (pPER3) was grown, and
the membranes were prepared by using a French press to make the
inner-membrane vesicles (outer membrane not formed with this
method).[13] All bilayers and cell walls were formed and rinsed in a
buffer solution that contained Tris chloride (20 mm ; pH 7.5; Tris =
tris(hydroxymethyl)aminomethane), ATP (1 mm), and MgCl2 (1 mm).
Soluble UDP MurNAc pentapeptide was isolated from the Bacillus
subtilis strain W23, HCINB 11824 (17-18). UDP GlcNAc was
obtained from Sigma (UK).
SPR experiments were performed in the Kretschmann configuration.[4b] A 50-nm layer of gold was thermally evaporated onto a
high-refractive-index glass prism, n = 1.847. Resonance curves were
obtained by recording the reflected intensity, R, that was normalized
with respect to the incident intensity, Ro, as a function of the angle of
incidence. Resonance curves were fitted by using a Levenberg–
Marquardt algorithm, assuming each layer to be optically isotropic.
With abrupt interfaces, a scattering-matrix method was used. The
aqueous ambient was assumed to have a refractive index of n = 1.333,
whereas that of the lipid, antibiotics, and peptidoglycan were assumed
to be 1.5.
Received: November 14, 2005
Revised: January 9, 2006
Published online: February 24, 2006
.
Keywords: antibiotics · bacterial cell wall · lipids · ramoplanin ·
vancomycin
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