Angewandte
Chemie
Abstract: Biocides are widely used for preventing the spread of
microbial infections and fouling of materials. Since their use
can build up microbial resistance and cause unpredictable
long-term environmental problems, new biocidal agents are
required. In this study, we demonstrate a concept in which an
antimicrobial polymer is deactivated by the cleavage of a single
group. Following the satellite group approach, a biocidal
quaternary ammonium group was linked through a poly(2-
methyloxazoline) to an ester satellite group. The polymer with
an octyl-3-propionoate satellite group shows very good anti-
microbial activity against Gram-positive bacterial strains. The
biocidal polymer was also found to have low hemotoxicity,
resulting in a high HC50/MIC value of 120 for S. aureus.
Cleaving the ester satellite group resulted in a 30-fold decrease
in antimicrobial activity, proving the concept valid. The
satellite group could also be cleaved by lipase showing that
the antimicrobial activity of the new biocidal polymers is
indeed bioswitchable.
contrast, biocidal polymers function as one molecule that is
able to destabilize and eventually destroy the cell membrane
of microorganisms resulting in cell lysis and cell death.[6,8a,b]
Thus, even antibiotic-resistant bacteria such as Methicillin-
resistent Staphylococcus aureus (MRSA) can be killed as
effectively as nonresistant S. aureus.[8c] The structure of
biocidal polymers, which by definition are composed of
nonbiocidal repeating units, is particularly interesting,
because full degradation of such polymers would inevitably
result in inactive compounds.[8d,e,13] A few examples of
potentially biodegradable biocidal polymers have been de-
scribed very recently.[9] Only one of them has actually been
explored regarding its degradation, showing deactivation only
under nonnatural conditions.[10] An alternative to the above-
mentioned polymers are biocides coupled as end groups to
inactive polymers.[8b,11] If the polymer contains a second, non-
antimicrobially active end group referred to as a satellite
group (SG), the antimicrobial activity of these polymers can
be controlled over several orders of magnitude.[8a] This might
offer the possibility of creating an antimicrobial polymer that
can be deactivated by altering a single bond in the whole
molecule. The idea is based on the fact that hydrophobic SGs
of appropriate length greatly activate the distal biocidal
group, whereas nonbasic hydrophilic groups deactivate it.
Thus, we chose to introduce an ester group as the SG, such
that the active macromolecule would be rendered inactive
just by the hydrolysis of this very function (Figure 1), possibly
biocatalyzed by anomnipresent lipase.
A
mong the most threatening health issues in modern
globalized society is the evolution of antibiotic-resistant
microorganisms.[1] Tremendous amounts of disinfectants are
used to fight pathogenic microbes but these weapons are
getting dull, because they help to build up microbial
resistance and are concentrated in the environment causing
unpredictable long-term problems[2,3a] either directly or by
their metabolites.[3] The optimal modern biocide would kill
germs in the targeted area for the required period of time and
then disappear.[4a] In the next best approach, a biocide would
biodegrade into an inactive, nontoxic form. So far, there are
only a few not fully accepted examples of biocides that are
degradable.[4]
The ester SG group was introduced at one polymer end by
a functional initiator, which was prepared by esterification of
3-bromopropanoic acid[12] and the respective alcohol, fol-
lowed by exchange of the bromide with iodide by a subsequent
Finkelstein reaction with NaI. Since the activity control of the
hydrophobic SG group is not easily predictable, a series of
ester initiators with various alkyl residues ranging from ethyl
to tetradecyl were been prepared (Table S1 in the Supporting
Information).
Antimicrobial polymers are a promising alternative to
low-molecular-weight antibiotics and disinfectants.[5] Such
macromolecules can be classified as biocide-releasing poly-
mers, polymeric biocides, and biocidal polymers.[6] A few
examples of the first two classes are designed to be
biodegradable, mostly to release biocides on demand.[7] In
The polymers were synthesized by cationic ring-opening
polymerization of 2-methyl-2-oxazoline (MOx) and termina-
tion with the known biocidal group N,N-dimethyldodecyl-
amine (DDA). All polymers were found to have more than
86% functionalization with SG as well as with the biocidal
[*] Dipl.-Ing. C. Krumm, Dipl.-Chem. S. Harmuth, M. Hijazi,
B. Neugebauer, A.-L. Kampmann, Prof. Dr. J. C. Tiller
Biomaterials and Polymer Science
1
Department of Bio- and Chemical Engineering, TU Dortmund
Emil-Figge-Strasse 66, 44227 Dortmund (Germany)
E-mail: joerg.tiller@udo.edu
DDA group according to H NMR spectroscopy.
Next, we tested whether the ester SG can be selectively
hydrolyzed. Thus, the polymer starting with octyl-3-iodopro-
panoate (OP) OP-PMOx-DDA was treated with 0.015m
aqueous NaOH at 508C overnight. The control experiment
was performed with an octyl bromide initiatedPMOx-DDA
(O-PMOx-DDA) described in previous work.[8a] According to
the 1H NMR spectra only OP-PMOx-SG was chemically
H. Geltenpoth, Prof. Dr. A. Sickmann
Leibniz-Institut fꢀr Analytische Wissenschaften –ISAS– e.V.
Otto Hahn-Strasse 6b, 44227 Dortmund (Germany)
[**] We thank Thorsten Moll for performing size-exclusion chromatog-
raphy and Dr. W. Hiller for performing 1H NMR measurements. We
also thank Andrea Breitkopf, Patrick Bolduan, and Shinthujah
Selvarasa for assistance in the laboratory and with the micro-
biological tests. All polymers were synthesized using CEM Discover
microwave reactors, which were kindly provided by CEM for
undergraduate student education. This work was supported by the
Ministerium fꢀr Innovation, Wissenschaft und Forschung des
Landes Nordrhein Westfalen and by grants from the Bildungsmi-
nisterium fꢀr Bildung und Forschung. We also thank the butcher
shop Niemann, Dortmund for providing the fresh porcine blood.
1
converted in the procedure (Figure S3). The H NMR spec-
trum of the NaOH-treated OP-PMOx-DDA (Figure S3b in
the Supporting Information) shows that the characteristic
octyl ester signals disappear after alkaline hydrolysis. All
other signals are not affected indicating that no other
modification took place.
Since 1H NMR data are not always sufficient to fully
characterize polymer chains, we performed electrospray
ionization mass spectrometry (ESI-MS) measurements of
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2014, 53, 3830 –3834
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3831