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Organic & Biomolecular Chemistry
Page 9 of 10
Journal Name
DOI: 10.1039/C5OB00830A
ARTICLE
the Promotion of Innovation through Science and Technology
in Flanders under grant IWT-SBO 120050 (NEMOA) and
through a PhD fellowship to S.R., the European Commission's
Seventh Framework Programme (FP7/2007(2013) under the
grant agreement COATIM (Project no. 278425), the KU Leuven
(IDO/11/008) and the F.W.O. (Fund for Scientific Research –
Flanders (Belgium)) through a postdoctoral fellowship to H.S.
The authors thank Wout Frederickx and Prof. Steven De Feyter
for AFM measurements, Koen Nuyts for helping in CD analysis,
Dr. Claudia Cavalluzzo for scientific discussions and theoretical
inputs, Prometa, KU leuven for MALDI-TOF measurements and
Dirk Henot for XRF analysis.
Figure 4a
Figure 4b
Figure 4. AFM-image of CRAMP in the absence of CuSO4·5H2O (Figure 4a) and in the
presence of CuSO4·5H2O (Figure 4b)
Notes and references
Table 5: Percentage of Cu and S present in CRAMP samples
Electronic Supplementary Information (ESI) is available, including
detailed experimental procedure and characterization of
compounds etc.
Samples
Amount of Cu
0.006%
Amount of
S
CRAMP pure (before treatment with
CuSO4·5H2O)
0.110%
1
a) B. Spellberg, R. Guidos, D. Gilbert, J. Bradley, H. W.
Boucher, W. M. Scheld, J. G. Bartlett and J. Edwards, Jr., Clin.
Infect. Dis. 2008, 46, 155-164; b) L. L. Silver, Clin. Microbiol.
Rev., 2011, 24, 71-109.
CRAMP peak-1 compound
0.010%
0.009%
0.250%
0.267%
CRAMP peak-2 compound
2
E. Mossialos, C. M. Morel, S. Edwards, J. Berenson, M.
Gemmill-Toyama, D. Brogan, Policies and incentives for
promoting innovation in antibiotic research, European
Observatory on health systems and policies ISBN 978 92 890
4213 0 , 2009.
Experimental
All the experimental procedures and schemes are given in the
supporting information.
3
4
5
6
7
8
9
R. E. W. Hancock and D. S. Chapple, Antimicrob. Agents
chemother. 1999, 43, 1317-1323.
Y. li, Q. Xiang, Q. Zhang, Y. Huang and Z. Su, Peptides 2012,
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B. Findlay, G. G. Zhanel and F. Schweizer, Antimicrob. Agents
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a) D. Vandamme, B. Landuyt, B. Luyten and L. Schoofs, Cell
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Conclusions
We aimed to synthesize a compound with broad-spectrum
antibacterial activity by conjugating an antibacterial peptide
with self-promoted uptake properties (CRAMP) and an
antibiotic that targets the cell wall synthesis (vancomycin). We
envisioned that CRAMP could function as a carrier molecule
for the transport of vancomycin through the outer membrane
of Gram-negative bacteria, while vancomycin could exert a
targeting function for CRAMP to enhance the affinity of
CRAMP for the cytoplasmic membrane. Short and hydrophobic
linkers bearing an aromatic group resulted in conjugates with
the best inhibitory properties. Whereas the effect was most
prominent for Gram-negatives, the conjugates with these
linkers also maintained their activity against some of the
tested Gram-positive bacteria comparable to vancomycin
alone. Biofilm formation was also strongly prevented with
these conjugates. Molecular mechanistic studies will be
needed in the future to elucidate if the carrier function, the
targeting function or both simultaneously explain the
improved antibacterial properties of the best conjugates.
10 M. Zanetti, J. Leukoc. Biol. 2004, 75, 39-48.
11 R. Ramos, L. Domingues and M. Gama, Science against
Microbial Pathogen: Communicating Current Research and
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12 B. Ramanathan, E. G. Davis, C. R. Ross and F. Blecha, Microb.
Infect. 2002, , 361-372.
13 C. Chamorro, M. A. Boerman, C. J. Arnusch, E. Breukink and
R. J. Pieters, Biochim. Biophys. Acta 2012, 1818, 2171-2174
14 a) R. C. James, J. G. Pierce, A. Okano, J. Xie, and D. L. Boger,
2, 915-925.
4
Chem. Biol. 2012,
ChemBioChem 2002,
Bardsley, Angew. Chem. Int. Ed. 1999, 38, 1172-1193; d) B. K.
7
3
,
797-804; b) R. D. Süssmuth,
, 295-298; c) D. H. Williams and B.
Acknowledgements
Hubbard and C. T. Walsh, Angew. Chem. Int. Ed. 2003, 42
730-765.
,
The authors wish to thank the Research Fund of the University
of Leuven (KU Leuven) for financial support. N.M. is grateful to 15 H. C. Neu and T. D. Gootz, ed. S. Baron, Medical
the Erasmus Mundus External Cooperation Window (EMECW),
Lot 13) and KU Leuven for a doctoral scholarship. J.V., H.S. and
S.R. are grateful for the funding received from the Institute for
Microbiology. 4th edn., Galveston (TX): University of Texas
Medical Branch at Galveston; 1996, Chap 11
This journal is © The Royal Society of Chemistry 20xx
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