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was previously reported (Trombetta
et al
.,
2002), similar to those found for alkyl gal-
lates (Fujita and Kubo, 2002). Interestingly,
2
E
-alkenals caused rapid CF leakage from
PC liposomes, and the effectiveness order
correlated well with the alkyl chain length.
Thus, 2
E
-nonenal was more effective in
inducing CF leakage from PC liposomes
than was 2
E
-hexenal (Trombetta
et al
.,
2002). This previous report also supports
the surfactant concept.
The activity often disappears after the
chain length reached the maximum activity
and this phenomenon is known as the cut-
off (Balgavy and Devínsky, 1996). As
expected, dodecanal (C12) was the most
effective against
S. choleraesuis
with both
MIC and MBC of 100 mg/ml, whereas tri-
decanal (C13) (
19
) did not show any activity
up to 800 mg/ml. Noticeably, this cutoff was
not observed with the 2
E
-alkenal series
against
S. choleraesuis
. That is, 2
E
-tridecenal
exhibits some activity, though to a lesser
extent than 2
E
-dodecenal. This difference
in susceptibility of
S. choleraesuis
to
2
E
-alkenals possessing different chain
lengths still remains largely unclear.
Because the hydrophobic forces are more
favourable than hydrogen-bonding forces,
this may help to explain the cutoff, in that
the compound is pulled further into the
membrane (Franks and Lieb, 1986) and
loses the orientation required for bilayer
disruption. Gram-negative bacteria includ-
ing
Salmonella
sp. surround themselves
with a double membrane. The inner or cyto-
plasmic membrane is mainly composed of
phospholipids, whereas the outer mem-
brane is an asymmetric structure containing
primarily phospholipids in its inner mono-
layer and lipopolysaccharide in its outer
monolayer (Snyder and McIntosh, 2000).
The outer membrane acts as an efficient per-
meability barrier against macromolecules
and hydrophobic substances (Helander
et al
., 1997). 2
E
-Alkenals at least overcome
the outer membrane barrier through the fol-
lowing mechanism of disruption and access
the cytoplasmic membrane. The hydrophilic
aldehyde group first binds with an intermol-
ecular hydrogen bond like a 'hook' by
attaching itself to the hydrophilic portion of
the cytoplasmic membrane surface, at which
point the hydrophobic alkyl portion of the
molecule is able to enter into the membrane
lipid bilayers (Kubo
et al
., 1995b).
The common nature among these alde-
hydes should be considered in that the elec-
tron negativity on the aldehyde oxygen
atom forms an intermolecular hydrogen
bond with a nucleophilic group in the mem-
brane, thereby creating disorder in the fluid
bilayer of the membrane. The fluidity of the
cell membrane can be disturbed maximally
by hydrophobic compounds of a particular
hydrophilic aldehyde group. They could
enter the molecular structure of the mem-
brane with the polar aldehyde group ori-
ented into the aqueous phase by hydrogen
bonding and non-polar carbon chain aligned
into the lipid phase by dispersion forces.
Eventually, when the dispersion force
becomes greater than the hydrogen-bonding
force, the balance is destroyed and the activ-
ity disappears. In connection with this, the
hydrophobic bonding energy between an
average fatty acid ester and a completely
hydrophobic peptide is approximately
12 kcal/mol. Addition of a hydrogen bond
between a peptide and a fatty ester's carbo-
nyl adds another 3-6 kcal/mol. Furthermore,
aldehydes first approach the binding site
with the electron negativity of the aldehyde
oxygen atom. This hydrogen bond acceptor
will affect the hydrogen bonds that regulate
the permeability of the lipid bilayer.
The process by which 2
E
-alkenals reach
the action sites in living microorganisms is
usually neglected in the cell-free experi-
ment but this must be taken into account in
the current study. The inner and outer sur-
faces of the membrane are hydrophilic,
whereas the interior is hydrophobic, so the
increased lipophilicity of 2
E
-alkenals
should affect their movement further into
the membrane lipid bilayer portions. It
should be logical to assume that most of the
lipophilic 2
E
-alkenal molecules being dis-
solved in the medium are partially incorpo-
rated into the lipid bilayers (Franks and
Lieb, 1986), in which they may react
with biologically important substances.
The amount of 2
E
-alkenals entering into the
cytosol or lipid bilayer is dependent on the
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