Letters in Applied Microbiology ISSN 0266-8254

ORIGINAL ARTICLE

Antimicrobial activity of carvacrol related to its chemical

structure
A. Ben Arfa1, S. Combes2, L. Preziosi-Belloy3, N. Gontard1 and P. Chalier1
1 UMR IATE (Agropolymers Engineering and Emerging Technologies), Universite Montpellier II, Montpellier France
2 UMR 6517 CNRS (Chimie, Biologie et Radicaux Libres), Universite dAix-Marseille 1 et 3, Faculte des Sciences de St Jerome, Marseille, France
3 UMR IR2B (Ingenierie des Reactions Biologiques et Bioprocedes), Universite Montpellier II, Montpellier, France

Keywords
antimicrobial activity, carvacrol, carvacryl
acetate, carvacrol methyl ether,
hydrophobicity, hydroxyl group.
Correspondence
P. Chalier, UMR IATE, Universite Montpellier
II, cc023, place Euge`ne Bataillon, 34095
Montpellier cedex 5, France. E-mail:
chalier@univ-montp2.fr

2005/1209: received 11 October 2005,

revised 9 March 2006 and accepted 14 March
2006
doi:10.1111/j.1472-765X.2006.01938.x

Abstract
Aims: To investigate the relation between the chemical structure and the antimicrobial activity of carvacrol, eugenol, menthol and two synthesized carvacrol
derivative compounds: carvacrol methyl ether and carvacryl acetate against bacteria, Escherichia coli, Pseudomonas fluorescens, Staphylococcus aureus, Lactobacillus plantarum, Bacillus subtilis, a yeast Saccharomyces cerevisiae and one fungi
Botrytis cinerea.
Methods and Results: The antimicrobial activity was tested in liquid and
vapour phases, by both broth liquid and microatmosphere methods, respectively. The same classification of the compounds antimicrobial efficiency was
found with both methods. Eugenol and menthol exhibited a weaker antimicrobial activity than carvacrol, the most hydrophobic compound. Carvacryl acetate
and carvacrol methyl ether were not efficient, indicating that the presence of a
free hydroxyl group is essential for antimicrobial activity.
Conclusions: The different extents of antimicrobial aroma compounds efficiency showed that hydrophobicity is an important factor and the presence of
a free hydroxyl group and a delocalized system allows proton exchange.
Significance and Impact of the Study: This study has identified the importance
of the hydrophobicity and the chemical structure of phenolic aroma compounds for antimicrobial activity and may contribute to a most rational use of
these compounds as antimicrobial agent.

Introduction
Essential oils isolated from plants are chiefly used as flavours or fragrances, but currently a renewal interest in
natural substances has focussed attention on plants rich
in bioactive compounds and essential oils well known for
their antimicrobial properties.
The antimicrobial activity of several essential oils has
been attributed to the presence of phenolic compounds,
i.e. the efficiency of thyme, clove and oregano essential
oils was assigned to thymol, eugenol and carvacrol,
respectively (Farag et al. 1989; Moleyar and Narasimham
1992; Kim et al. 1995b; Tsao and Zhou 2000; Lambert
et al. 2001). The inhibitory effect of phenols could be

explained by interactions with the cell membrane of

micro-organisms and is often correlated with the hydrophobicity of the compounds (Sikkema et al. 1995; Weber
and de Bont 1996). For instance, oregano essential oil was
reported to induce permeability alteration in the microorganisms membranes (Pseudomonas aeruginosa, Staphylococcus aureus) with a consequent leakage of protons,
phosphates and potassium (Lambert et al. 2001). Among
phenolic compounds, carvacrol, an isoprenyl phenol, was
reported to have one of the strongest antimicrobial activity (Kim et al. 1995a; Roller and Sheedhar 2002).
In order to use carvacrol as antimicrobial agent in food
preservation in a rational way, a good knowledge of its
mode of action is required. For example, it is well known

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Antimicrobial activity of carvacrol

A.B. Arfa et al.

that grafting an antimicrobial peptide on a polymer could

strongly reduce its antimicrobial efficiency (Appendini
and Hotchkiss 2001).
The aim of this study is to improve the understanding
of carvacrol action mode, with a focus on both its hydrophobicity and the presence of hydroxyl group, in order to
promote its use in adequate conditions to fully maintain
its antimicrobial efficiency. Antimicrobial properties of
carvacrol and four other compounds of different chemical
structures: eugenol, a methoxy-phenol, menthol, a terpenyl alcohol and two specifically synthesized compounds
derived from carvacrol (carvacryl acetate and carvacrol
methyl ether) were evaluated both in liquid and in
vapour state on a range of different micro-organisms.
Results are discussed and compared in relation with the
hydrophobic and structural characteristics of the tested
compounds.
Materials and methods
Aroma compounds
Carvacrol, eugenol and menthol were purchased from
Fluka, Chemika, Sigma-Aldrich (St Quentin Fallavier,
France). The compounds purity was about 97%. Due to
its solid state at ambient temperature, menthol was dissolved in ethanol absolute (1 : 1).

methyl ether was clearly identified by NMR study. The

1
H NMR data (obtained in deuterated tricloromethane),
such as H chemical shift position and coupling constant
were provided: dH 125 [6H, s, J 70 Hz, (CH3)2CH],
dH 218 (3H, s, CH3), dH 287 [1H, sept, J 70 Hz,
(CH3)2CH], 383 (3H, s, OCH3), 670 (1H, d, J 15 Hz,
6-H), 673 (1H, dd, J 75 Hz and 15, 4-H) and 705
(1H, d, J 75 Hz, 3-H).
Carvacryl acetate
A mixture of carvacrol (30 g, 20 mmol), sodium acetate
(37 g, 45 mmol) and acetic anhydride (20 ml, 02 mol)
was heated at 110
C overnight. The mixture was concentrated under vacuum, diluted with water and extracted
with dichloromethane. The organic layer was washed with
water, and dried over Na2SO4. The solvent was distilled
off and the residue purified by column chromatography
(eluant C5H12-Et2O, 95 : 5) to afford carvacryl acetate
(292 g, 76%) as colourless oil (bp 238
C/750 mmHg).
The structure of the compound was confirmed by proton
NMR study. 1H NMR (CDCl3): dH 123 [6H, s, J
69 Hz, (CH3)2CH], 213 (3H, s, CH3), 231 (3H, s, OCOCH3), 287 [1H, sept, J 69 Hz, (CH3)2CH], 685
(1H, d, J 15 Hz, 6-H), 701 (1H, dd, J 78 Hz and
15 Hz, 4-H) and 714 (1H, d, J 78 Hz, 3-H).
Strains and growth conditions

Carvacrol methyl ether and carvacryl acetate synthesis

General
All solvents were purified by standard techniques. Separation by column chromatography was performed using
Merck Kieselgel 60 (70230 mesh). NMR spectra were
obtained on a Bruker AC 300 spectrometer. Chemical
shifts (d) are reported in parts per million for a solution
of the compound in CDCl3 (in deuterated trichloromethane) with internal reference Me4Si and protonproton
coupling constant (J-values) are expressed in Hertz.
Carvacrol methyl ether
A mixture of carvacrol (30 g, 20 mmol), potassium carbonate (272 g, 20 mmol) and dimethylsulfate (19 ml,
20 mmol) in dry acetone (10 ml) was refluxed overnight.
The mixture was cooled, filtrated and the solvent was distilled off under reduced pressure. The residue was dissolved in ether (100 ml), washed with 10% aqueous
NaOH (3 30 ml), then with water and dried over anhydrous Na2SO4. The solvent was removed under vacuum
and the residue was purified by column chromatography
(eluant C5H12) to afford carvacrol methyl ether (28 g,
88%) as colourless oil (bp 100
C/12 mmHg). Carvacrol
150

Strains used in this study were Escherichia coli

(I.P.54127), Pseudomonas fluorescens (I.P.6913), Staph.
aureus (I.P.53126), Lactobacillus plantarum (I.P.1406),
Bacillus subtilis (I.P.7718), Saccharomyces cerevisiae
(CBS.400), Botrytis cinerea (MUVCL.30158). Bacteria and
yeast were kept at )80
C in 20% (v/v) glycerol, while
mould was kept on petri dishes at 4
C.
Nutrient broth and plate count agar media (Biokar
Diagnostic, Beauvais, France) were used as a basal medium for E. coli, P. fluorescens, Staph. aureus and B. subtilis,
while L. plantarum was cultivated on Man Rogosa and
Sharp (MRS; Biokar Diagnostic, Beauvais, France) and S.
cerevisiae on yeast extract glucose (YEG; Biokar Diagnostic). Yeast and bacteria strains were first inoculated in the
appropriate broth for 24 h; subsequently, cells from this
culture were inoculated in fresh medium and incubated
at 30
C for 16 h, in order to obtain 108109 cells ml)1.
Potato dextrose agar medium (PDA; Biokar Diagnostic)
was used as basal medium for the growth of fungi. Spores
of 7-day-old cultures were first harvested in sterile distilled water with 01% (v/v) tween 80. The concentration
of the conidia suspensions was determined using a haemocytometer (Malassez cell) under an optical microscope
at 400 magnification. Experiments with the fungi were

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A.B. Arfa et al.

only carried out in vapour phase by microatmosphere

method.
For microatmosphere tests, media were first sterilized
in flasks and cooled down to 45
C and kept at this temperature for 1 h. A volume of 15 ml of agar medium was
poured into sterile petri dishes of 9-cm diameter and left
at 22
C for 16 h before use.
Antimicrobial activity of the aroma compounds
The antimicrobial activity of the selected aroma compounds was analysed in liquid phase by broth liquid
method and in vapour phase by microatmosphere
method. Each experiment was carried out at least in triplicate.
Determination of aroma compounds minimal inhibitory
concentration in liquid phase
A range of each aroma compound concentrations (01,
025, 05, 1, 2, 3 g l)1) was tested on the growth of
micro-organisms. A defined quantity of pure aroma compound was homogeneously deposited on a sterilized filter
paper (05 5 cm corresponding to the height of the
medium in the tube), which was immediately introduced
into the tube containing 10 ml of a fresh liquid medium.
The medium was then inoculated with 100 ll of the
microbial suspension (108109 cells ml)1).
Two types of controls were made with filter paper
impregnated with 3 g l)1 of ethanol only (solvent use for
menthol dissolution) and with sterilized filter paper alone.
Tests and controls were incubated at 30
C for 48 h and
no growth inhibition was observed with the two controls.
Micro-organism growth was monitored visually and
was observed after 48 h by a cloudy medium. The lowest
concentration of aroma compounds required to inhibit
the growth of micro-organisms was designated as the
minimum inhibitory concentration (MIC). When growth
inhibition was observed at the MIC after 48 h, subcultures were made to determine the cidal effect. A volume
of 100 ll from the broth was sprayed on agar medium
surface (in the appropriate medium) in a petri dish. Incubation was carried out at 30
C for 48 h and colony-forming units (CFU) were counted.
Determination of aroma compounds minimal inhibitory
dose in vapour phase
For yeast and bacteria, cell suspensions of 105
106 cells ml)1 were prepared by serial dilutions in sterile
tryptone salt and five dots of each suspension (10 ll)
were put on agar surface. For fungi, 104 spores were
inoculated in the centre of the petri dish.
Increasing quantities (25, 5, 10, 15, 20, 30 mg) of
aroma compounds were dissolved in 500-ll of ethyl acet-

Antimicrobial activity of carvacrol

ate and deposited homogenously on sterilized filter papers

(63 cm2). These papers were put in the lid of petri dishes,
which were turned upside down. Controls made with
papers impregnated with ethyl acetate alone induced no
inhibition growth. The incubation conditions of the petri
dishes were 48 h at 30
C for yeast and bacteria or 15 days
at 22
C for the fungi. These tests were based on the presence or absence of growth, which was assessed visually.
The minimal inhibition dose (MID) is defined as the
minimal dose of aroma compounds required to completely inhibit yeast and bacteria growth for 48 h and
fungi for 15 days.
Results
In addition to carvacrol, four other compounds with different chemical structures were tested for their antimicrobial activities. Two carvacrol derivative compounds were
specifically synthesized: carvacrol methyl ether and carvacryl acetate, containing an ether and an ester group,
respectively instead of the hydroxyl group of carvacrol.
Eugenol, a methoxy phenol, possesses a free hydroxyl
group but the delocalized system is different from that of
carvacrol due to the presence of the methoxyl group.
With regard to menthol, it is a terpenyl alcohol and in
contrast to the other compounds, it has no delocalized
system, but it possesses a free hydroxyl group. The physico-chemical characteristics of the aroma compounds and
their chemical structures are presented in Table 1.
The MIC of carvacrol, eugenol, menthol, carvacryl acetate and carvacrol methyl ether was determined by broth
liquid method and are reported in Table 2. The maximal
concentration tested was 3 g l)1, and above this concentration, the aroma compound was regarded as inefficient.
According to the literature, the MIC range varied from
025 to 25 g l)1 depending on the micro-organisms
genus and on experimental conditions (Kim et al. 1995b;
Chang et al. 2001; Iscan et al. 2002).
None of the five tested compounds were able to inhibit
the growth of L. plantarum, a bacteria particularly well
known for its resistance (Ouattara et al. 1997). Eugenol
and carvacrol had similar antimicrobial activity against
P. fluorescens. However, eugenol and menthol were clearly
less efficient than carvacrol against the other microorganisms, especially against Staph. aureus and B. subtilis.
Moreover, it should be noted that MIC induced a cidal
effect, since no microbial growth (colonies) was observed
when test samples were inoculated on agar plates. Both
carvacrol derivatives could not inhibit the micro-organism growth: only one inhibition was observed towards
S. cerevisiae by the ether at the maximal concentration
(3 g l)1). In complement, the effect of the aroma compounds was performed in vapour phase by microatmos-

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Table 1 Physico-chemical characteristics and molecular structure of the studied aroma compounds at 25
C
Aroma
compounds

Molecular
structure

Molecular weight
(g mol)1)

Vapour pressure
25
C (Pa)

LogP*

Maximum solubility
in water (g l)1)

Carvacrol

15022

64

352

011

Carvacrol
methyl ether

162

408

0033

Carvacryl acetate

192

35

359

0097

Eugenol

16421

39

273

064

Menthol

15627

163

338

015

25

*Octanol/water partition coefficient (logP) was estimated by modelling soft: http://esc.syrres.com/interkow/examples.htm.

Solubility was calculated from this equation: logSg )095 logP + 240 (Valvani et al. 1980).

phere method (Table 3) and led to similar conclusions

about the ineffectiveness of the synthesized compounds.
Carvacrol was the most efficient compound, followed by
eugenol and menthol. Both derivative-synthesized compounds were inefficient against all the micro-organisms
tested.
Discussion
The inhibitory action of aroma compounds is, in most
cases, related to the hydrophobicity, which is directly correlated to the logP (partitioning behaviour of the lipophilic compounds in octanol/water) and on their partition in
152

the cytoplasmic microbial membranes (Lanciotti et al.

2003). The most hydrophobic compounds are generally
reported to be the most toxic and the cytoplasmic membrane is often the primary site of toxic action (Sikkema
et al. 1995; Weber and de Bont 1996). Indeed, lipophilic
compounds possess a high affinity for cell membranes
and their insertions induce changes in membrane physico-chemical properties. The interactions between antimicrobial compounds and cell membranes are described
to affect both the lipid ordering and the bilayer stability,
resulting in a membrane integrity decrease and an
increase of proton passive flux across the membrane. This
effect is particularly reported with compound with a logP

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A.B. Arfa et al.

Antimicrobial activity of carvacrol

Table 2 Minimal inhibition concentration (g l)1) of the aroma compounds tested by broth liquid method

Strains

Carvacrol

Carvacryl Carvacrol
acetate methyl ether Eugenol Menthol

Pseudomonas
fluorescens
Escherichia coli
Staphylococcus
aureus
Bacillus subtilis
Lactobacillus
plantarum
Saccharomyces
cerevisiae

>3

>3

025
025

>3
>3

>3
>3

05
1

05
1

025
>3

>3
>3

>3
>3

025

>3

1
>3

1
>3

05

05

Table 3 Minimal inhibitory dose (mg per petri dish) of the aroma
compounds tested by microatmosphere method

Strains

Carvacryl Carvacrol
Carvacrol acetate methyl ether Eugenol Menthol

Pseudomonas 10
fluorescens
Escherichia coli 5
Staphylococcus 5
aureus
Bacillus subtilis 10
Lactobacillus
20
plantarum
Saccharomyces 5
cerevisiae
Botrytis cinerea 5

>30

>30

>30

>30

>30
>30

>30
>30

10
5

30
30

>30
>30

>30
>30

15
>30

20
>30

>30

>30

10

20

>30

>30

10

>30

higher than 3. In agreement, carvacrol, which has a logP

of 352 (Table 1) was found to be the most efficient antimicrobial compound. Eugenol showed a lower efficiency
than carvacrol mainly towards E. coli, Staph. aureus,
B. subtilis and S. cerevisiae growth. This weakest antimicrobial activity could be attributed to its lower hydrophobicity less than 3 (273) expressed through the logP.
Carvacrol methyl ether has a high logP; however, it did
not inhibit the growth of the tested micro-organisms in
the studied conditions. The absence of antimicrobial
activity of this compound was previously reported by
Ultee et al. (2002): B. cereus growth was not inhibited at
a concentration of 10 mmol l)1 of carvacrol methyl ether
(19 g l)1), whereas carvacrol was efficient at a lower concentration of about 075 mmol l)1 (011 g l)1). Moreover,
the antimicrobial activity of carvacrol and its methyl ether
has been compared against different strains using Iso-Sensitest agar and measured by the growth inhibition diameter; carvacrol methyl ether was clearly less efficient than
carvacrol (Dorman and Deans 1999).

Vermue et al. (1993) showed that a high logP did not

always result in the greater toxicity of the compounds.
Compounds with a logP higher than 4 are generally not
toxic; because of their insolubility they cannot reach a
toxic concentration in the cell membrane.
Carvacryl acetate has a logP of 359 and thus hydrophobicity equivalent to carvacrol, but exhibited no effect
on micro-organism growth. In the same way, menthol
has a logP higher than 3 and slightly lower than carvacrol
log-P value, but yet exhibited a weak effect on microorganism growth. These results indicated that another
factor other than hydrophobicity must be involved.
Ultee et al. (2002) hypothesized that the hydroxyl
group and the presence of a system of delocalized electrons are important for the antimicrobial activity of phenolic compounds, such as carvacrol and thymol. Such a
particular structure would allow compounds to act as
proton exchanger, thereby reducing the gradient across
the cytoplasmic membrane. The resulting collapse of the
proton motrice force and depletion of the ATP pool lead
eventually to cell death.
The key role of free hydroxyl group of aromatic compounds on micro-organism growth inhibition is fully supported by the aforementioned results on carvacrol and
carvacryl acetate antimicrobial effect. Indeed, as they
exhibited a similar hydrophobicity, the main difference
between the acetate and carvacrol is the binding of the
hydroxyl group. The inefficiency of the other compound
deprived of the hydroxyl group, the carvacrol methyl
ether, has already been observed by Ultee et al. (2002),
but could be discussed regarding its different and very
high hydrophobicity.
The importance of a delocalized electron system allowing hydroxyl group to release its proton, is supported by
the observed low antimicrobial effect of menthol compared with carvacrol (Tables 2 and 3), in agreement with
the results of Ultee et al. (2002). In contrast, the delocalized electron system present in carvacryl acetate and carvacrol methyl ether implied that they are proton
acceptors, but they are not able to release a proton
through the ester or the ether group. Moreover, the weak
antimicrobial effect of eugenol, attributed earlier to its
low hydrophobicity could be also due to the presence of
a methoxyl group in ortho position, unabling the OH
group to release easily its proton.
In conclusion, the present study fully supported the
hypothesis that in addition to the hydrophobic characteristic allowing the compound accumulation in the membrane, free hydroxyl function proved to be essential for
the antimicrobial activity of carvacrol.
Moreover, this hydroxyl group must be able to
exchange its proton, thanks to an adequate delocalized
electron system.

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Thanks to its appropriate hydrophobicity, carvacrol can

be accumulated in the cell membrane. Its hydrogen-bonding ability and its proton-release ability may induce conformational modification of the membrane resulting in
the cell death. In contrast, the absence of a free hydroxyl
group in carvacryl acetate and carvacrol methyl ether may
prevent them from exchanging their proton, from modifying membrane permeability and thus from inducing
micro-organism growth inhibition.
Knowing this mode of action, particular attention
should be paid to preserve or if possible to improve these
key factors when using such phenolic aroma compounds
for their antimicrobial properties.
Acknowledgements
The authors want to gratefully acknowledge Ahlstrom
Research and Services and the Ministe`re de lEnseignement Superieur et de la Recherche for the financial support to this work.
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