HIGHLIGHT www.rsc.

org/npr | Natural Product Reports

Bacterial pathways for degradation of nitroaromatics

Zoe C. Symons and Neil C. Bruce*
Received (in Cambridge, UK) 27th June 2005
First published as an Advance Article on the web 6th October 2006
DOI: 10.1039/b502796a

Covering: up to 2006

The last one hundred years have seen a massive expansion in the chemicals industry; however, with this
progress came the concomitant pollution of the environment with a significant range of xenobiotics.
Nitroaromatic compounds form one such category of novel environmental contaminants and are
produced through a large number of industrial processes, most notably the pesticides, dyes and
explosives industries. Whilst singly nitrated aromatic compounds are usually mineralised in the
environment, multiply nitrated aromatics, such as the explosive 2,4,6-trinitrotoluene (TNT), are
recalcitrant and highly toxic. The predominant route of biological transformation of aromatic
compounds is oxidation; however, the presence of three electron-withdrawing nitro-groups around the
ring prevents oxidation, rendering such compounds resistant to biodegradation. The subsequent
accumulation of these contaminants has stimulated much research leading to the isolation of bacteria
that possess, to varying extents, the ability to remediate explosives and other nitroaromatic pollutants.
The extreme environments created by these toxic substances accelerate the evolutionary process and
examples of bacteria that have conscripted metabolic enzymes for novel remediatory pathways are
included. This Highlight ends with a discussion of the future of nitroaromatic bioremediation including
engineering plants to express bacterial enzymes for use in bioremediation programs.

Introduction Dinitrotoluene (DNT), an intermediate in TNT manufacture

The chemical versatility of the nitrogroup means nitroaromatic
compounds are widely used in industry in the synthesis of
dyestuffs, pesticides, explosives and polyurethane foams. Ni-
troaromatics also form the basis of explosives such as 2,4,6-
trinitrotoluene (TNT) and 2,4,6-trinitrophenol (picric acid)
and have historically been produced on a massive scale. 2,4-
CNAP, The Department of Biology, AREA 8, The University of York, PO
Box 373, York, England YO10 5YW. E-mail: ncb5@york.ac.uk; Fax: 44-
(0)1904 328801; Tel: 44-(0)1904 328777
and starting material for the synthesis of toluene diisocyanate,
is also produced on a large scale. The extensive use of many
nitroaromatic compounds in such chemical processes has led to
their widespread contamination of the environment. Five hundred
thousand U. S. gallons of water, contaminated with trinitrotoluene
and other nitroaromatics, may be released into the environment
by one TNT-manufacturing plant in one day.1 At some munitions
manufacturing and processing sites the contamination can be
as high as 200g TNT per 1 kg of soil.2 Many of the multiply-
nitrated compounds are cytotoxic and have been classified as
probable carcinogens. TNT, for example, is documented as causing

Zoe Symons obtained her Master of Biochemistry from the University of Bath, studied for her PhD at the Institute of Biotechnology,
University of Cambridge, and is currently a post-doctoral research fellow in CNAP, University of York.

Neil Bruce is currently Professor of Biotechnology at CNAP in the

Department of Biology at the University of York. Following a PhD
in Microbial Biochemistry at the University of Kent in 1987, he
joined the Institute of Biotechnology at the University of Cambridge
as a postdoctoral research associate with Prof. Chris Lowe and was
subsequently awarded a Research Fellowship at Wolfson College. He
was appointed to a University Lectureship in Biotechnology in the same
department in 1990 and subsequently appointed to a Fellowship at Trinity
Hall. He was promoted to a Personal Readership in Biotechnology in
2001. In 2002 he was appointed to the Chair of Biotechnology at the
University of York. The major research themes of his laboratory are
microbial metabolism, biocatalysis and environmental biotechnology.

Zoe C. Symons Neil C. Bruce

This journal is © The Royal Society of Chemistry 2006 Nat. Prod. Rep., 2006, 23, 845–850 | 845
erythrocyte abnormalities, dysfunction of the liver and cancer to utilise this compound as a carbon source for growth is quite
in mammals. Unfortunately, once released into the environment remarkable.
many of these compounds persist for long periods of time. The enzymes which form the pathway have been characterised
This is likely to be because similar compounds rarely occur individually and their reactions are illustrated in Fig. 1.
in the Natural world, their structural novelty rendering them
resistant to breakdown as indigenous organisms have no means of
metabolising them.3
The inherent toxicity of these anthropogenic compounds means
they should not be permitted to remain in the environment;
however, the widespread contamination of the soil and ground
water worldwide means that inexpensive and sustainable tech-
nologies to remove these toxic compounds need to be developed
and employed. Current methods of remediating contaminated
sites, such as incineration and composting, can be expensive
and harmful. Incineration of soil to rid it of explosives can
result in the exposure of workers to high levels of toxins.3,4,5 One
solution to the problem of nitroaromatic contamination, which
is considered both economically feasible and environmentally
sound, is bioremediation. This is the use of organisms, such as
microbes or plants, to degrade or detoxify hazardous materials. To
these ends research groups have employed selective enrichments,
with the nitroaromatic supplied as the sole carbon and/or nitrogen
source for growth, to isolate “specialist” microbes with the ability
to transform nitroaromatics. In this way, bacteria and fungi have
been isolated with the ability to transform nitroaromatic com-
pounds. Enzymes responsible for conferring the nitroaromatic-
transforming activity on a number of microbes have been cloned
and characterised, offering an enhanced understanding of the bac-
terial metabolism of nitroaromatics—the subject of this Highlight.

Enzymes associated with nitroaromatic transformation

Many enzymes have been characterised as being capable of trans-
forming nitroaromatic compounds via oxidative and reductive
attack. These include monooxygenases, dioxygenases, hydride
transferases and nitroreductases. Most recently, an iron-only
hydrogenase from Clostridium acetobutylicum has also been shown
capable of reducing TNT to its dihydroxylamino derivative in a
hydrogen-dependent manner and has been demonstrated to be
responsible for the great extent of the nitroreductase activity of C. Fig. 1 The metabolism of 2,4-dinitrotoluene catalysed by Burkholderia
acetobutylicum.6 cepacia R34, adapted from Johnson et al.7 Compounds in brackets remain
hypothetical.

The evolution of nitroaromatic degradation pathways

Recent work on the biodegradation of dinitrotoluene by
Burkholderia cepacia R34 offers one of the most elegant examples
of how bacteria have evolved to not only tolerate but to metabolise
nitroaromatic compounds as a nutrient source for growth.7 B.
cepacia R34 was isolated from surface water from an ammunition
plant and was therefore subject to significant environmental selec-
tive pressures. Analysis of the enzymes it employs to transform 2,4-
DNT has revealed that the bacterium has co-opted enzymes from
diverse pre-existing pathways to produce one specific to 2,4-DNT.7
The genes encoding the enzymes required for degradation are
found on a contiguous 27 kb region of DNA, which also includes
regions devoted to the regulation of the pathway. Considering that
2,4-DNT has only been produced for the last one hundred years
the ability of bacteria to piece together a new metabolic pathway
The first denitration is catalysed by DNT dioxygenase (encoded
by dntAaAbAcAd), a Rieske non-haem iron oxygenase recruited
from a naphthalene degradation pathway. This oxygenase has
three parts, an oxidoreductase (Aa), an iron-sulfur ferredoxin pro-
tein (Ab) and a terminal oxygenase centre (Ac and Ad form a and
b subunits). The second denitration is catalysed by the 4-methyl-
5-nitrocatechol monooxygenase (dntB) believed to be seconded
from a degradation pathway originally for chloroaromatic com-
pounds. The 2,4,5-trihydroxytoluene then undergoes ring fission
catalysed by 2,4,5-trihydroxytoluene oxygenase (dntD). The 2,4-
dihydroxy-5-methyl-6-oxo-2,4-hexadienoic acid, the ring fission
product, is metabolised by the enzyme dntG to yield pyruvate and
methylmalonic acid semialdehyde in turn transformed by dntE,
although the final product propionyl-CoA remains hypothetical.
All the last three enzymes have been hijacked from amino acid

846 | Nat. Prod. Rep., 2006, 23, 845–850 This journal is © The Royal Society of Chemistry 2006
degradation pathways. The enzymes which form this novel 2,4-
DNT degradation pathway are all encoded on a single contiguous
length of DNA, producing a pathway specific to an anthropogenic
compound.
The correct functioning of a pathway that has adapted or been
created to transform nitroaromatic compounds relies not only
on possessing enzymes with the appropriate catalytic activity but
also on the expression of these enzymes in the presence of the
nitroaromatic compound. The first example of a nitroaromatic-
triggered lys–R transcriptional activator was reported recently.8
Two nitroarene dioxygenases were studied, nitrobenzene dioxyge-
nase (NBDO) in Comomonas sp. strain JS765 and 2-nitrotoluene
dioxygenase (2NTDO) from Acidovorax sp. strain JS42. They are
under the control of identical Lys–R related proteins, NbzR and
NtdR, homologous to the previously reported NahR.
The work revealed the expression of 2NTDO and NBDO can
be induced by a plethora of nitroaromatic compounds including
nitrobenzene, 2-, 3- and 4-nitrotoluene, 2,4- and 2,6-dinitrotoluene
and aminodinitrotoluenes in addition to the endogenous salicylate
and anthranilate. The metabolism of these compounds was not
necessary for induction suggesting the nitroaromatic compounds
themselves are the actual effector molecules with the NtdR
essential for induction. This represents a pathway in evolution.
Enzymes capable of transforming nitroaromatic compounds are
being organised to be expressed in response to the presence
of these novel substrates, although at present the regulatory
proteins still respond to their endogenous effectors salicylate and
anthranilate.
Nitrogen assimilation by bacteria has also been studied with ref-
erence to TNT degradation. Recent work employing Pseudomonas
putida JLR11 has shown that the nitrogen containing products
released on TNT degradation are assimilated via the glutamine
synthetase–glutamate synthase (GS–GOGAT) pathway.9

The metabolism of naturally occurring nitroaromatic
compounds
Very few naturally occurring nitroaromatic compounds are
known. Recently, for the first time, the degradation pathway
of one of these compounds, 3-nitrotyrosine, a product of the
interaction between reactive nitrogen species and amino acids,
was elucidated.10 Using 3-nitrotyrosine as sole growth substrate in
soil enrichment cultures, multiple bacteria were isolated capable
of catalysing the degradation of 3-nitrotyrosine with the release
of nitrite and ammonia. Two species, Burkholderia sp. strain
JS165 and Variovorax paradoxus JS171 were chosen for further
study.
The pathway for the breakdown of 3-nitrotyrosine was found
to be both separate from the tyrosine degradation pathway and
inducible in its entirety by cell growth on 3-nitrotyrosine or
its breakdown product 4-hydroxy-3-nitro-phenylacetate (HNPA)
(Fig. 2).
The pathway starts with an a-ketoglutarate dependent deam-
ination to produce the conjectural intermediate 4-hydroxy-
3-nitrophenyl pyruvate. This is decarboxylated to yield HNPA,
in turn denitrated to homoprotocatechuate by a monooxygenase.
The homoprotocatechuate is cleaved by homoprotocatechuate-
2,3-dioxygenase to yield 5-carboxymethyl-2-hydroxy-cis,cis-
Fig. 2 The proposed pathway for the breakdown of the naturally occur-
ring nitroaromatic compound 3-nitrotyrosine, adapted from Nishino and
Spain.10 Compounds in brackets are proposed intermediate compounds.
muconic semialdehyde, the metabolism of which has been
thoroughly characterised. This pathway utilised for 3-nitrotyrosine
metabolism has been demonstrated to be analogous to the tyro-
sine degradation pathway, which also proceeds via homoproto-
catechuate, and may have derived from the tyrosine pathway.
Nitroreductases
The enzymatic transformation of triply nitrated aromatic com-
pounds, such as the explosives TNT and picric acid, is gener-
ally limited to reductive transformations. Enzymes capable of
catalysing such reactions are exemplified by the Enterobacter
cloacae PB2 enzyme, PETN reductase (PETNr), a monomeric
40 kDa flavoenzyme,11,12 which is capable of catalysing both the
nitroreduction of TNT and the ring reduction, as illustrated in
Fig. 3.
PETNr was isolated through its ability to confer resistance
to PETN, a nitrate ester explosive, on the bacterium.11 PETNr
was found to be a member of the Old Yellow Enzyme family
of flavoenzymes and was the first of a series of enzymes from

This journal is © The Royal Society of Chemistry 2006 Nat. Prod. Rep., 2006, 23, 845–850 | 847

Fig. 3 The biotransformation of 2,4,6-trinitrotoluene as catalysed by
PETN reductase from Enterobacter cloacae PB2.
this family that have since proven capable of transforming
explosives.12–16 PETNr is capable of reductively liberating nitrite
not only from PETN and nitroglycerine, but from nitroaromatic
explosives such as TNT and picric acid. The nitroreduction of
triply nitrated aromatics (Fig. 3, Pathway A) is more common.
Many bacteria/enzymes have proven capable of opportunistic
nitroreduction of nitroaromatic compounds. A recent example
is that of PnrA,17 an NADPH dependent nitroreductase, ho-
mologous to nfsA, the Escherichia coli nitroreductase, capable
of transforming TNT to yield 4-hydroxylamino-2,6-DNT via a
ping-pong bi–bi mechanism. It is capable of reducing multiple
nitroaromatic substrates including 2,4-DNT, 3-nitrotoluene, 3-
and 4-nitrobenzoate, 3,5-dinitrobenzamide and 3,5-dinitroaniline,
although it was most efficient with TNT.
The nitroreduction of TNT results in the production of
metabolites that are still toxic. Hydroxylamino-dinitrotoluenes
(HADNTs) damage DNA causing mutations18 and result in
the redox cycling of the TNT derivatives with the concomitant
production of harmful reactive oxygen species.19 This has been
put to good use in the field of cancer therapy as discussed later.
Interestingly, the nitroso intermediate inherent in this pathway
has not been isolated. Recent work testing the nfsB encoded
E. coli nitroreductase against nitroso- and nitro-toluene and
benzene (Fig. 4) demonstrated that the nitrosoderivatives are
far better substrates for the enzyme, having specificity constants
20–30 000 times that of the nitro-substrates.20 This offers an
explanation as to why the nitrosoderivatives of these and other
nitrocompounds are seldom seen in biotransformations.
848 | Nat. Prod. Rep., 2006, 23, 845–850
Fig. 4 The structures of nitro- and nitroso-toluene and benzene.
Hydride transferases
A second reductive biotransformation of TNT (Fig. 3, Pathway B)
has been observed, which offers hope for the complete degradation
of TNT. It is catalysed by some members of the Old Yellow Enzyme
family16,21,22 including PETNr. This second pathway features the
reduction of the aromatic ring of TNT. Aromatic transformations
are intuitively associated with oxidative attack due to the high
electron density of the benzene ring; however, the three NO2
groups present in TNT are sufficiently electron-withdrawing to
render the ring electron-poor and subject to reductive attack. The
result is the production of hydride- and dihydride-Meisenheimer
TNT complexes (H− -TNT and 2H− -TNT) and hence the loss
of aromaticity. The ultimate products of the pathway are not
known; however, the reduction of the dihydride-Meisenheimer
TNT complexes has been confirmed to be enzyme-catalysed,23 and
in the course of the transformation, nitrite is released. The final
transformation products remain elusive, although recent work has
characterised them as lacking visible absorbance and being highly
polar. They contain less nitrogen than TNT, are non-aromatic and
water soluble, all of which suggests that they will be less recalcitrant
to degradation and less toxic than both TNT and the products of
the nitroreduction pathway.5,16
A second example of such a hydride transfer reaction with a
nitroaromatic compound comes in the form of picric acid degra-
dation by Rhodococcus (opacus) erythropolis and Nocardiodes
simplex FJ2–1A, reviewed in Heiss and Knackmuss24 (Fig. 5).
Picric acid is more easily degraded than TNT. Substantial
work characterising the entire pathway of picric acid degradation
has been performed by the Knackmuss group in their work on
Rhodococcus (opacus) erythropolis HL PM-1 and Nocardioides
simplex FJ2–1A.24–27 The initial reaction is hydride addition to
the aromatic ring, to create a hydride Meisenheimer complex,
as discussed with TNT; however, with picric acid no nitrore-
duction is observed, only the hydride addition as catalysed
by a F420 -dependent hydride transferase (NpdI) and its F420
reductase (NpdG).25,27 A second hydride addition is catalysed by
NpdC/NpdG in R. (opacus) erythropolis; whereas, in N. simplex,
both hydride transfers are catalysed by the same enzyme.
Following the production of the dihydride Meisenheimer com-
plex it is hypothesised that the multiple products observed are due
to the tautomerisation of the protonated dihydride Meisenheimer
complex, catalysed by NpdH.27 The hydride Meisenheimer com-
plex of 2,4-dinitrophenol has been identified as an intermediate
of picric acid degradation in Nocardioides sp. strain CB 22–2,
which would suggest that nitrite is released from the dihydride
Meisenheimer complex or one of its protonated tautomers.24 Inter-
estingly, R. erythropolis can also catalyse the ring hydrogenation
This journal is © The Royal Society of Chemistry 2006

Fig. 5 The transformation of picric acid by Rhodococcus (opacus)
erythropolis HL–PM1, adapted from Heiss and Knackmuss.24
of TNT, similar to the reaction catalysed by PETNr; however,
unlike PETNr, in spite of the production of 2H− -TNT, no nitrite
release is observed.28
Bacterial enzymes applied
It seems that the most widespread source of nitroaromatic pollu-
tion is from the explosives industry, either through the active use
of explosives or through the manufacture and decommissioning of
munitions. Having characterised bacteria capable of transforming
and degrading explosives it seems a logical next step to use these
bacteria to remove the toxic explosives from soil. There are,
however, disadvantages in using bacteria for this purpose. Firstly,
when in competition with the local bacterial ecosystem, in non-
optimal growth conditions, there may be a significant drop in
the biomass of the applied bacteria. Equally, co-metabolism can
necessitate the addition of extra substrates to induce the enzyme
required for pollutant transformation.29 Additionally, although
many strains of explosives-detoxifying microorganisms have been
isolated from contaminated soil, pollution remains a problem
at these sites. This can be overcome using genetic engineering;
however, overwhelming anti-GMO public opinion makes such
This journal is © The Royal Society of Chemistry 2006
a course of action difficult with genetically modified microbes.
Considerable research has been devoted to the phytoremediation
of explosives, that is using plants to biotransform explosives. Plants
are uniquely suited to the removal of explosives contamination
due to their penetrating root systems, comparably high biomass
and compatibility with restorative ecology. Original work sought
to employ genetically unmodified plant species in this process;
however, major disadvantages were the inherently low levels of
detoxification coupled with the susceptibility of these plants to
the toxicity of the explosives. For phytoremediation to be a com-
petitive alternative to current methods of explosives degradation,
plants need to efficiently take up the contaminants and break
them down or transform them to less toxic intermediates. This has
been achieved by the constitutive expression of bacterial enzymes
in plants.30 The expression of both nitroreductase and PETN
reductase from Enterobacter cloacae PB2 has been achieved in
arabidopsis and tobacco plants. The resultant PETNr plants could
survive in concentrations of GTN and TNT (1 mM and 0.05 mM
respectively) that were toxic to genetically unmodified tobacco
plants.30 Similarly, aromatic nitroreductases, when expressed in
plants, provided even greater resistance to the toxic effects of
TNT.31
Bacterial enzymes are similarly being used outside their natural
environment in novel cancer therapies. Most particularly E. coli
oxygen insensitive nitroreductase (nfsB) is being used to activate ni-
troaromatic compounds, such as the dinitrobenzamide prodrugs,
to their cytotoxic hydroxylamino derivatives to destroy tumours.
Mammalian nitroreductases do not catalyse the activation of these
compounds, so the bacterial nitroreductases, when targeted to
the tumour using ADEPT (antibody directed enzyme prodrug
therapy) or GDEPT (gene-directed enzyme prodrug therapy),
exclusively activate the compounds in the vicinity of cancerous
growth. Recent determination of the nitroreductase structure in
complex with a series of these dinitrobenzamide drugs now paves
the way not only for the rational design of novel prodrugs but
also for the rational design of the enzyme specifically for cancer
therapies.32
Conclusions
An understanding of the bacterial transformation of nitroaro-
matic compounds has clear benefits for bioremediation research,
medicine and industry. In addition to a more detailed understand-
ing of how the initial nitroaromatic oxidases or reductases operate,
an enhanced appreciation of the role of enzymes that function
downstream of these initial attack enzymes will facilitate the
optimisation of remediation pathways through the upregulation of
key downstream metabolic enzymes. In addition to a contribution
to the field of bioremediation, the elucidation of dissimilation
pathways for nitroaromatic compounds is likely to continue to
furnish a rich source of enzymes as biocatalysts for the synthesis
of high value chemicals and drugs.
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This journal is © The Royal Society of Chemistry 2006