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REVIEW ARTICLE
Tellurite: history, oxidative stress, and molecular mechanisms
of resistance
Thomas Girard Chasteen1, Derie Esteban Fuentes2, Juan Carlos Tantaleán3 & Claudio Christian Vásquez2
1
Department of Chemistry, Sam Houston State University, Huntsville, TX, USA; 2Laboratorio de Microbiologı́a Molecular, Departamento de Biologı́a,
Facultad de Quı́mica y Biologı́a, Universidad de Santiago de Chile, Santiago, Chile; and 3Laboratorio de Microbiologı́a y Biotecnologı́a,
Universidad San Luis Gonzaga, Ica, Peru
Correspondence: Claudio Christian Vásquez,
Laboratorio de Microbiologı́a Molecular,
Departamento de Biologı́a, Facultad de
Quı́mica y Biologı́a, Universidad de Santiago
de Chile, Casilla 40, Correo 33, Santiago,
Chile. Tel.: 156 2 718 1117; fax: 156 2 681
2108; e-mail: [email protected]
Received 1 July 2008; revised 5 February 2009;
accepted 1 March 2009.
Final version published online 2 April 2009.
DOI:10.1111/j.1574-6976.2009.00177.x
Editor: Bernardo Gonzalez
Keywords
tellurite; Escherichia coli; chalcogen; reactive
oxygen species; thiol; metalloid.
Abstract
The perceived importance of tellurium (Te) in biological systems has lagged
behind selenium (Se), its lighter sister in the Group 16 chalcogens, because of
tellurium’s lower crustal abundance, lower oxyanion solubility and biospheric
mobility and the fact that, unlike Se, Te has yet to be found to be an essential trace
element. Te applications in electronics, optics, batteries and mining industries have
expanded during the last few years, leading to an increase in environmental Te
contamination, thus renewing biological interest in Te toxicity. This chalcogen is
rarely found in the nontoxic, elemental state (Te0), but its soluble oxyanions,
tellurite (TeO23 ) and tellurate (TeO24 ), are toxic for most forms of life even at very
low concentrations. Although a number of Te resistance determinants (TelR) have
been identified in plasmids or in the bacterial chromosome of different species of
bacteria, the genetic and/or biochemical basis underlying bacterial TeO23 toxicity
is still poorly understood. This review traces the history of Te in its biological
interactions, its enigmatic toxicity, importance in cellular oxidative stress, and
interaction in cysteine metabolism.
Introduction
Historical background
Tellurium (Te) was discovered by Müller in 1782 (Dittmer,
2003) in work with Hungarian gold mines. The metalloid
was named 16 years later after the Latin word for earth, tellus
(Weeks, 1956) (tellos in Greek). The initial discovery was not
so much a determination of a new element as an exclusion of
other alternatives, the last being proof that the element,
which Müller had isolated from Transylvanian gold ore, was
not antimony. Somewhat surprisingly, this isolation came 35
years before the lighter, sister metalloid selenium’s discovery
by Berzelius in 1817. Sulfur had been known since ancient
times and oxygen was isolated in 1774 (Weeks, 1956).
Oxygen, sulfur, selenium, and tellurium are collectively
referred to as chalcogens (Fischer, 2001).
As is characteristic of most of the metalloids, tellurium’s
oxyanions are relatively stable. Environmentally, tellurite
(TeO23 ) is most abundant, with tellurate’s low solubility
(TeO24 ) limiting its concentration in biospheric waters.
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Elemental tellurium (Te0) is insoluble and found as black
deposits in some bacterial-selective growth media (Chasteen
& Bentley, 2003; Amoozegar et al., 2008). Gold ores containing Te are calaverite (AuTe2), sylvanite (AgAuTe4), and
nagyagite [AuPb(Sb, Bi)Te2–3S6] (Cairnes, 1911). Te is often
found associated with copper- and sulfur-bearing ores
(Pan & Xie, 2001; Whiteley & Murray, 2005) and so Te is most
commonly commercially obtained as a byproduct of copper
refining (Dittmer, 2003). Bismuth/tellurium minerals such as
tellurobismuthite (Bi2Te3) or wehrite (Bi2Te2) (Cook & Ciobanu, 2004; Laitinen & Oilunkaniemi, 2005) may figure into
the story of ‘bismuth breath’ described below.
The biological interaction with inorganic Te compounds was
initially reported by Gmelin, who described the olfactory
detection of ‘odorous compounds’ in the breath of animals
exposed to inorganic Te (Gmelin, 1824). This report influenced
the experimental design by Hansen in the mid-1800s – investigating the garlic-like odor in the breath of humans and dogs
exposed to TeO23 – who experimented upon himself by taking
30–80 mg doses of TeO23 and postulated that the smelly gaseous
compound emitted was diethyl telluride (Hansen, 1853).
FEMS Microbiol Rev 33 (2009) 820–832
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Toxicity of and bacterial resistance to tellurite
This 19th-century experimental exuberance was repeated
by Reisert in his pursuit of ‘bismuth breath’, a ‘disagreeable
garlic-like odor’ emanating from humans who have ingested
bismuth (Bi) salts (Reisert, 1884). When ingested, purified
bismuth nitrate yielded no odor from dosed subjects.
However, ingested TeO2 at doses as small as 6 mg produced
detectable garlic-like odors from human breath that lasted
30 h. Reisert’s analogous As-ingestion experiments selfadministered on the author, although producing ‘griping’
stomach pains after 4 days of daily, 12 mg arsenous
oxide, produced no garlic-like breath odors, leading to the
report that these odors were not caused by Bi, but by traces
of Te in Bi samples from Bi2Te3. Reisert reiterated Hansen’s
suggestion that the gaseous, biologically produced
compound was CH3CH2TeCH2CH3, but cogently noted
that dimethyl telluride also smelled like garlic. Hofmeister
(1894) later also made this connection and claimed dimethyl
telluride detection – from biological sources – based
strictly on smell.
Bird & Challenger (1939) identified the volatile, strongsmelling compound as dimethyl telluride, CH3TeCH3. Mead
& Giles (1901) had reported CH3TeCH3 in the breath of
mammals dosed with Te oxyanions and in the breath of a
chemist who, synthesizing large batches of TeO2, had
apparently inhaled the dust. Inhalation of a large dosage led
to depression and long periods of sleep as well as strong
outgassing of dimethyl telluride (from breath, sweat, and
feces), smells that last for months and, in one case, a year
after exposure (Mead & Giles, 1901). The unenviable subject
was Victor Lenher at Columbia University in New York, who
was engaged in early studies on Te0 (Lenher, 1899, 1900).
Both Klett (1900) and Scheurlen (1900) reported the
production of black or gray insoluble Te0 in microorganisms
amended with TeO23 . Later, this would be proven using
X-ray diffraction analysis (Tucker et al., 1962). This resulted
from the biological reduction of soluble Te(IV) to the
insoluble, elemental form and led to an interesting use of
Te0 formation as a microbiological test: building on Gosio’s
(1905) work, Corper (1915) produced a rapid test of
viability for the organism that caused human tuberculosis.
When a sterile sodium tellurite solution was added to cells
thought to be viable human tubercle bacilli and incubated at
37 1C, a visible blackening occurred within 30–120 min if the
culture was live. Corper (1915) was interested in avoiding
expensive work with dead cultures in his work on the
biochemistry and chemotherapy of tuberculosis (Chasteen
& Bentley, 2003). Alexander Fleming, the discoverer of
penicillin in the 1920s, also used tellurite-amended media
to differentially isolate bacteria (Fleming, 1942). Davis
(1914) and Cavazutti (1921) had noted much earlier that
different bacterial species and strains exhibited widely
differing resistance to TeO23 exposure. Davis (1914) also
suggested using TeO23 for a differential diagnosis.
FEMS Microbiol Rev 33 (2009) 820–832
Assessment of the toxicity of Te-containing compounds
was systematically performed over half a century ago, with
the general conclusion that the simplest salts containing
TeO23 (e.g. Na2TeO3) were more toxic to most organisms
than TeO24 (Fleming, 1932, 1942; Franke & Moxon, 1936;
Cooper & Few, 1952; Schroeder et al., 1967). Munn &
Hopkins (1925), who examined silver ammonium tellurite
and potassium iodotellurite as bacterial disinfectants, found
them to be comparable to silver nitrate, and Frazer (1930)
found intramuscular injections of suspensions of Te0 in
glucose to be successful in the treatment of human syphilis;
however, one substantial drawback was an intense garlic
odor in the patients’ breath and urine. De Meio (1946) also
noted garlic exhalations from rats dosed with Te0 and,
subsequently, reported that ascorbic acid administered to
both rats and humans dosed with Te0 reduced the garlic
breath (De Meio, 1947). Ascorbic acid was used to treat
industrial workers (exposed to Te-containing dust) who
exhibited ‘chronic constant garlic breath,’ and it was reported that odoriferous symptoms were completely eliminated or greatly reduced by taking daily vitamin C
treatments, but the symptoms returned when the doses of
vitamin C were halted. De Meio (1947) proposed that
ascorbic acid reduced oxidized Te back to Te0 before it
entered the biological pathway for methylation.
In 1945, Frederic Challenger published his seminal review
entitled ‘Biological Methylation,’ focusing on the biological
interaction of organisms with arsenic, selenium, and tellurium, among others (Challenger, 1945; Chasteen & Bentley,
2003; Zannoni et al., 2008). The mechanism he proposed for
the sequential reduction and methylation of Se, he also
proposed for Te. Fig. 1 details those steps, beginning with
H2TeO3 and yielding CH3TeCH3. A modification of this
mechanism to explain the production of dimethyl selenenyl
sulfide, CH3SeSCH3, has also been proposed (Chasteen,
1993). Recent detection of CH3TeSCH3, dimethyl tellurenyl
sulfide, in the headspace of a bacterial culture amended with
sodium tellurite makes this mechanism plausible for Te too
(Swearingen et al., 2004).
It has been proposed that the reduction and methylation
of toxic, metalloidal oxyanions is a detoxification
Fig. 1. Challenger’s Te reduction and methylation mechanism.
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822
mechanism because the volatile end products are less toxic
than the initial oxyanions (McConnell & Portman, 1952;
Wilber, 1980; Frankenberger & Arshad, 2001; Chasteen &
Bentley, 2003). In investigations of the Se mechanism, one of
the Se intermediates, dimethyl selenone [(CH3)2SeO2], has
been synthesized and its toxicity has been measured (Fig. 1).
Using bacterial growth inhibition as a means of probing
relativity toxicity, (CH3)2SeO2 was found to be less toxic
than either selenite or selenate (Yu et al., 1997).
More recently, as Se was recognized as an essential element
(Stadtman, 1996; Chasteen & Bentley, 2003), workers began to
investigate the role of Te in biological systems. Schroeder et al.
(1967) reported that a typical human being possessed 4 0.5 g
of Te, mostly in bone, and this exceeds the levels of all other
trace elements in humans, except for iron, zinc, and rubidium.
In the development of a so-called Biological System of the
Elements, Markert (1992, 1994) proposed that Te, long
thought to be toxic, will eventually be found to be an essential
element in a manner similar to Se. This was more recently
echoed by Chasteen & Bentley (2003).
Until the advent of GC-MS, the identity of the garlic-like
odor produced by bacterial cultures amended with Te salts
was based primarily on the smell itself or by wet chemical
tests designed to trap a bacterial-produced gas, derivatize it,
and compare the derivative’s melting point with a standard
(Bird & Challenger, 1939). Fleming & Alexander (1972) used
GC-MS to confirm the production of both CH3SeCH3 and
CH3TeCH3 by metalloid-amended Penicillium sp.
The enigma of TeO23 toxicity
Although rarely found in nature, the tellurium oxyanion,
TeO23 , is highly toxic for most bacteria at concentrations as
low as 1 mg mL 1 (Taylor, 1999). This figure is even more
significant when compared with other metals and metalloids
such as selenium, chromium, iron, mercury, cadmium, and
copper, which become toxic at concentrations about 100fold higher than that of TeO23 (Nies, 1999). For example, in
Escherichia coli, the toxic effects of TeO23 begin at concentrations several orders of magnitude lower than the standard
determined for heavy metals that are of public health and
environmental concern such as cobalt, zinc, and chromium
(Nies, 1999; Harrison et al., 2004a).
During the last few years, Te applications in electronics,
optics, batteries, and mining industries have expanded,
which has indirectly led to increased environmental Te
contamination, allowing the isolation of a number of
naturally occurring tellurite-resistant bacteria from clinical
(Bradley, 1985; Taylor, 1999) and environmental samples
(Summers & Jacoby, 1977; Tantaleán et al., 2003).
A number of genetic Te resistance determinants (TelR)
have been identified in different species of bacteria that can
be found in plasmids or in the bacterial chromosome. In
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T.G. Chasteen et al.
general, these determinants mediate TeO23 resistance by an
as yet unknown mechanism.
Analysis of the nucleotide and the deduced amino acid
sequences of the TelR determinants has shown a considerable
degree of diversity that has hampered the proposal of a
universal TeO23 resistance mechanism. A few putative TeO23
resistance mechanisms have been proposed to date, but they
are not supported by definitive experimental evidence. The
proposed mechanisms include direct extrusion of TeO23 ,
TeO23 conversion to volatile, alkylated forms, and enzymatic
or nonenzymatic reduction of TeO23 (Te41) to insoluble Te0.
With regard to the mechanism of direct extrusion of TeO23 ,
it became clear that it does not constitute a true resistance
mechanism, as a decreased influx or an increased efflux of
TeO23 is not responsible for the K2TeO3 resistance of E. coli
cells expressing TelR determinants (Turner et al., 1995a).
In general, most microorganisms share the ability to
reduce TeO23 (Te41) to the less toxic, Te0. This results in
the generation of black deposits of metallic Te inside the cell.
At this point, it is important to emphasize that there is a
difference between microbial TeO23 resistance and TeO23
reduction. Several tellurite-sensitive microorganisms, for
example E. coli K12, are also able to reduce TeO23 (Summers
& Jacoby, 1977; Avazeri et al., 1997). Work by Van FleetStalder et al. (2000), using X-ray absorption spectroscopy,
confirmed Se0 production by Rhodobacter sphaeroides. Later,
Harrison et al. (2004b) described the production of Te0 and
Se0 in Staphylococcus aureus and Pseudomonas aeruginosa. It
has been suggested that a flavine-dependent reductase,
located at the plasma membrane, could play an essential
role in TeO23 reduction (Moore & Kaplan, 1992). Similarly,
Chiong et al. (1988) and Moscoso et al. (1998) documented
the ability of some Gram-negative and Gram-positive thermophilic bacteria to reduce this toxic salt. Enzymatic
activities present in crude extracts of these microorganisms
were found to be NAD(P)H-dependent [Fig. 2(2)]. In
addition, in vivo and in vitro TeO23 reduction by E. coli
dihydrolipoamide dehydrogenase has been demonstrated
recently (Castro et al., 2008).
Apparently, differences between tellurite-sensitive and
tellurite-resistant organisms can be associated with mechanisms that cause oxyanion extrusion or by biochemical
modifications different from reduction. In the latter case,
the generation of methylated forms of Te and Se has been
detected in the headspace of recombinant E. coli strains
carrying genes of the Gram-positive bacilli Geobacillus
stearothermophilus. Methyl telluride is volatile and therefore
would be easily eliminated from the cell (Araya et al., 2004;
Swearingen et al., 2006) [Fig. 2(13)].
In any case, little is known regarding TeO23 resistance
mechanisms in microorganisms. To date, five genetic TelR
determinants have been characterized in Gram-negative
bacteria. Interestingly, four of them were found in plasmids,
FEMS Microbiol Rev 33 (2009) 820–832
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Toxicity of and bacterial resistance to tellurite
Fig. 2. A model that illustrates our vision of the participation of certain enzymes (or some of their products) of the cysteine biosynthetic pathway in
K2TeO3 resistance. Cys, cysteine; CysK, cysteine synthase; [Fe–S], iron-sulfur center; GSH and GSSG, reduced and oxidized glutathione, respectively;
IscS, cysteine desulfurase; OAS, O-acetyl-L-serine; RSH and RSSR, reduced and oxidized thiol, respectively; SOD, superoxide dismutase; SUMT,
S-adenosyl-L-methionine uroporphirynogen III C-methyltransferase; YqhD, aldehyde reductase; ZWF, glucose-6-phosphate dehydrogenase; ACN,
aconitase; FUM, fumarase; LpdA, E3 component of the pyruvate dehydrogenase; YggE, antioxidant protein; UbiE, C-methyl transferase; SoxRS,
oxidative stress regulon (superoxide sensitive); OxyR, oxidative stress regulon (hydrogen peroxide sensitive). To exert its toxicity, TeO23 must enter the
target cell, most probably through the phosphate entry route (1). Part of the incoming TeO23 is reduced by nitrate reductase (2). In addition, reduced
thiols (3), catalase (20), dihydrolipoamide dehydrogenase (4), and other unspecific reductases can reduce TeO23 . TeO23 reduction to Te0 generates
superoxide; increasing ROS levels trigger oxidative stress (5). ROS increase generates cellular damage (6). Superoxide anion generated during TeO23
reduction damages [Fe–S] centers in proteins and enzymes (aconitase and fumarase) (7). Released Fe can generate hydroxyl radical (OH) through
Fenton or Habèr–Weiss reactions (8). IscS desulfurase participates in the recovery of [Fe–S] centers (9). TeO23 reduction decreases reduced thiols, which
are restored at the cost of NADPH (10). CysK contributes to restore the intracellular RSH pool (11). SUMT participates in the biosynthesis of the siroheme
prosthetic group of sulfite reductase (12). The TeO23 reduction product (Te0) could be further eliminated as alkylated volatile forms of Te by UbiE
methyltransferase (13). Generated OH causes macromolecular damage, especially to DNA (14). Superoxide can initiate membrane lipid peroxidation
and protein oxidation (15,16). YqhD detoxifies the cell from reactive aldehydes derived from membrane lipid peroxidation (17). YggE would decrease
superoxide levels (18). Increased SOD levels allow superoxide dismutation (19). H2O2 generated by superoxide dismutation is decomposed by catalase
(20). Tellurite-generated stress induces the expression of the SoxRS regulon (21). zwf gene induction by SoxRS would allow restoring the NADPH pool
(22).
which are important for the transference of resistance
determinants between species. The presence of TelR determinants in a wide range of bacterial species, including those
pathogenic for humans, suggests that these determinants
provide some selective advantage in their natural environment (Walter & Taylor, 1992; Hill et al., 1993). However,
these determinants might not have evolved specifically to
provide TeO23 resistance. For example, IncHI2 and IncHII
conjugative plasmids carrying the ter operon confer highlevel TeO23 resistance as well as resistance to bacteriophages
and colicins (Whelan et al., 1995; Taylor, 1999; Taylor et al.,
2002). In this context, besides the genetic variability
observed in E. coli O157 clinical isolates, several putative
TeO23 determinants have been found in cross searches by
homology in other bacteria such as Yersinia pestis and
Deinococcus radiodurans (Taylor, 1999; Taylor et al., 2002).
FEMS Microbiol Rev 33 (2009) 820–832
As mentioned above, TeO23 resistance determinants
found in extrachromosomal elements include IncHI-2
(Whelan et al., 1995, 1997) and pMER610 (Jobling &
Ritchie, 1987, 1988; Hill et al., 1993) plasmids. The unique
structure of the Klebsiella pneumoniae TerB protein (151
amino acid residues, KP-TerB) has recently been determined
(Chiang et al., 2008). Other examples are the kilA operon
(klaA klaB telB) from the RK2/RP4 plasmid, involved in
plasmid partition and maintenance (Goncharoff et al., 1991;
Walter et al., 1991; Turner et al., 1995b), and the ars operon
from the E. coli R773 plasmid (Turner et al., 1992). The kilA
operon present in Klebsiella aerogenes plasmid pRK2TeR
(accession # M62846), pTB11 plasmid (AJ744860), P. aeruginosa pBS228 plasmid (AM261760) and pWFRT-tel
(EU329006) and mini-Tn7-tel (EU626136) cloning vectors
share 99–100% sequence identity and encode KlaA, KlaB,
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824
and KlaC polypeptides of 257, 378, and 317 amino acid
residues, respectively. The genetic and protein contexts are
identical and genes are apparently transcribed as an operon.
Recently, kilA telAB sequences have been used as selection
markers to engineer cloning vehicles for Burkholderia spp.
(Barrett et al., 2008). Regarding the arsenical efflux pump, it
has been proposed that ArsC is involved in modifying the
substrate-binding site of the anion-translocating ATPase,
thus conferring moderate levels of resistance to TeO23
(Turner et al., 1992).
On the other hand, Taylor et al. (1994) reported that a
fifth TelR determinant, represented by the tehAB operon and
located near the terminus of the E. coli chromosome,
conferred resistance to potassium tellurite in this bacterium,
provided these genes are expressed from a multicopy
plasmid (Taylor et al., 1994). Later, Turner et al. (1997)
demonstrated that the 36-kDa integral membrane protein
TehA confers resistance to antiseptics and disinfectants
similar to that conferred by multidrug resistance efflux
pumps. More recently, the presence of the resistance determinant tehAB, by an as yet unidentified mechanism, was
found to protect the cells from uncoupling by TeO23
(Lohmeier-Vogel et al., 2004).
TehA and TehB orthologs have been found in a number
of bacteria including K. pneumoniae (accession #
YP_002238239 and YP_002238240, respectively), Salmonella enterica serovar Typhi (CAD01716 and CAD01717),
Shigella dysenteriae (YP_403356 and YP_403355), Shigella
flexneri (YP_689245 and YP_689244), Haemophilus influenzae (YP_248222 and YP_249313), Pasteurella multocida
(NP_ 246526 and NP_245593), S. enterica serovar Typhimurium (NP_460568 and NP_460567), Mannheimia succiniproducens (YP_087218 and YP_088530), and Escherichia
albertii (ZP_02902738 and ZP_02902769), among others.
Recently, the crystal structures of TehB from Vibrio fischeri
(PDB ID: 3DL3) and Corynebacterium glutamicum (PDB
ID: 3CGG) have been made available.
It is interesting to note that there is little homology among
the nucleotide sequences of these five TelR determinants. Apart
from arsRDABC, which encodes an oxyanion efflux system,
mechanisms by which all other TelR determinants specify
TeO23 resistance are a matter of speculation to date.
Using a different approach, a number of research groups
have reported that overexpressing some genes involved in
basal metabolism results in an increased tolerance to TeO23 .
For example, cloned cysK genes (encoding cysteine synthase)
from G. stearothermophilus V (Vásquez et al., 2001), S. aureus
(Lithgow et al., 2004), E. coli (Alonso et al., 2000), and
R. sphaeroides (O’Gara et al., 1997) mediate TeO23 resistance
when expressed in heterologous hosts [Fig. 2(11)].
A possible explanation for these findings may lie in the
intrinsic mechanism of TeO23 toxicity. It is known that Te
(and Se) oxyanions interact with cellular thiols (RSH), and
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T.G. Chasteen et al.
it has been found that glutathione (GSH) is one of the most
important targets of TeO23 in E. coli (Spallholz, 1994; Turner
et al., 2001). Based on the similarity between Se and
Te chemistry, it was postulated that GSH can reduce TeO23
to Te0 (Turner et al., 2001).
On the other hand, it was postulated that superoxide
could be generated during TeO23 reduction [Fig. 2(5)] as
occurs for selenite oxyanions (SeO23 ) (Bébien et al., 2002;
Kessi & Hanselmann, 2004). Even though this last possibility
has been supported in recent communications (Tantaleán
et al., 2003; Borsetti et al., 2005; Rojas & Vásquez, 2005;
Calderón et al., 2006), direct experimental evidence was only
recently obtained for Pseudomonas pseudoalcaligenes KF707
(Tremaroli et al., 2007) and E. coli (Pérez et al., 2007), where
the amount of mRNA transcripts of genes specifically
commanded by the transcriptional OxyR and SoxS regulators and the activity of classic antioxidant enzymes such as
superoxide dismutase and catalase [Fig. 2(19–20)] were
found to be increased as a consequence of TeO23 exposure
(Pérez et al., 2007). Thus, an emerging view for the TeO23
toxicity problem is that bacteria seem to cope with the
toxicity by a general adaptation mechanism like those used
when they face other environmental stressors such as UV
radiation or heat shock, among others (Fig. 2). A summary
of genes known to be involved in TeO23 resistance or
sensitivity is listed in Table 1. Another group of metabolic
genes that seems to participate actively in TeO23 metabolism
includes acnA, acnB, fumA, and fumC, among others
(C. Vásquez, unpublished data).
Bacterial mechanisms against oxidative stress
and TeO23 tolerance
Bacteria have evolved several mechanisms to protect themselves from environmental stress. The increase in reactive
oxygen species (ROS) during oxidative stress leads to thiol
oxidation, among other effects. Some of these thiols form part
of cellular proteins such as the OxyR transcriptional regulator,
which is transitorily activated by disulfide linkage formation
under oxidative stress (Zheng et al., 1998). In E. coli, OxyR
regulates the expression of several H2O2-inducible genes
encoding for enzymes known to participate in the bacterial
response to oxidative stress (Zheng et al., 2001). Examples of
these enzymes are hydroperoxidase I (encoded by katG),
alquil-hydroperoxide reductase (ahpCF), glutathione reductase (gorA), glutaredoxin 1 (grxA), thioredoxin 2 (trxC), iron
uptake regulator (fur), an unspecific DNA-binding protein
(dps), external membrane protein (agn43) and ferric reductase
(fhuF), among others (Storz & Imlay, 1999).
In addition, several E. coli genes are regulated by the
soxRS transcriptional regulatory system that responds to
superoxide-generating species. These genes include sodA
(Mn-dependent superoxide dismutase), nfo (endonuclease
FEMS Microbiol Rev 33 (2009) 820–832
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Toxicity of and bacterial resistance to tellurite
Table 1. Genes involved in tellurite resistance (R) or sensitivity (S)
Gene symbol
Function
R/S
Organism
References
arsABC
aceE, aceF
choQ
CSD (cdsA)
cobA
csdB
cysM
cysK
Metalloid efflux
Central metabolism
Amino acid transport
Cysteine metabolism
Siroheme biosynthesis
Cysteine metabolism
Cysteine metabolism
Cysteine metabolism
R
R
S
S
R
R
R
R
gutS
ibpA
iscS
katA
katG
kilA, telA,telB
(klaA, klaB, klaC)
lpdA
mntH
narGHIJ
phoB, phoR ?
pstA, pstD
sodAB
soxS
tehA, tehB
terBCDE
terC
tmp
trgAB
trmA
ubiE
yqhD
Tellurite/selenite-induced transporter
Heat-shock response
Cysteine metabolism
Hydrogen peroxide detoxification
Hydrogen peroxide detoxification
Tellurite resistance
ND
S
R
R
R
R
E. coli
E. coli
Lactococcus lactis
E. coli
E. coli
E. coli
E. coli
E. coli, Rhodobacter sphaeroides,
G. stearothermophilus
E. coli
E. coli
E. coli
Staphylococcus epidermidis
E. coli
E. coli
Central metabolism
Mn12/Fe12 transport
Nitrate reduction
Phosphate metabolism
Phosphate transport
Superoxide detoxification
Oxidative stress response
Tellurite resistance
Tellurite resistance
Tellurite resistance
Purine metabolism
Tellurite resistance
Heat-shock response
Ubiquinone/menaquinone biosynthesis
Oxidative stress response
R
S
R
R
S
R
R
R
R
R
R
R
S
R
R
A. caviae
L. lactis
E. coli
E. coli
L. lactis
E. coli
E. coli
E. coli
E. coli
Proteus mirabilis
P. syringae
R. sphaeroides
L. lactis
G. stearothermophilus
E. coli
Turner et al. (1992)
Castro et al. (2009)
Turner et al. (2007)
Rojas & Vásquez (2005)
Araya et al. (2009)
Rojas & Vásquez (2005)
Lithgow et al. (2004)
O’Gara et al. (1997), Alonso et al. (2000),
Vásquez et al. (2001), Fuentes et al. (2007)
Guzzo & Dubow (2000)
Pérez et al. (2007)
Tantaleán et al. (2003), Rojas & Vásquez (2005)
Calderón et al. (2006)
Pérez et al. (2007)
Goncharoff et al. (1991), Turner et al. (1995b),
Walter et al. (1991)
Castro et al. (2008)
Turner et al. (2007)
Avazeri et al. (1997)
Tomás & Kay (1986)
Turner et al. (2007)
Tantaleán et al. (2003), Pérez et al. (2007)
Pérez et al. (2007)
Taylor et al. (1994), Turner et al. (1995b)
Kormutakova et al. (2000)
Toptchieva et al. (2003)
Cournoyer et al. (1998)
O’Gara et al. (1997)
Turner et al. (2007)
Araya et al. (2004)
Pérez et al. (2008)
ND, not defined.
IV, involved in DNA repair), zwf (glucose-6-phosphate
dehydrogenase), tolC (outer membrane protein), fur, micF
(regulatory RNA of ompF expression), acrAB (multidrug
efflux pump), fumC (fumarase C), acnA (aconitase A), nfsA
(nitroreductase A), fpr (ferredoxin/flavodoxin reductase),
fldA, fldB (flavodoxin A and B), and ribA (GTP hydrolase)
(Liochev et al., 1999; Storz & Imlay, 1999).
In general, exposure to low stress levels or to some
chemicals induces an increase in an organism’s resistance to
subsequent expositions to the same (adaptative response) or
to unrelated (cross-response) agents (Mongkolsuk et al.,
1997). In this sense, both types of responses (OxyR and
SoxRS) have been shown to play an important role in
bacterial oxidative stress and in the stress generated by toxic
metals as well. For instance, low concentrations of cadmium
induce a synergistic protection against death by hydrogen
peroxide in Xanthomonas campestris (Banjerdkij et al.,
2005). In turn, sublethal concentrations of selenite activate
an adaptive response that increases SeO23 tolerance and
induces crossed protection to the ROS elicitor paraquat in E.
FEMS Microbiol Rev 33 (2009) 820–832
coli (Bébien et al., 2002). Conversely, treatment with sublethal concentrations of TeO23 did not show cross-protection against the oxidant compounds paraquat, diamide or
hydrogen peroxide in P. pseudoalcaligenes KF707 (Tremaroli
et al., 2007). These results differ from those observed in
E. coli K-12. Pérez et al. (2007) found a cooperative-like
toxicity effect between TeO23 and these oxidants as well as
an activation of the transcription of oxyR- and soxS-regulated genes, suggesting a synergistic protection against these
toxic compounds.
Preliminary results from our laboratory indicate that
E. coli cells exposed to paraquat exhibit increased minimal
inhibitory concentrations of TeO23 , suggesting an adaptative
response of the bacterium. In addition, a clinical isolate of
Proteus mirabilis showed increased tolerance to potassium
TeO23 when previously grown in media containing sublethal
TeO23 concentrations (Toptchieva et al., 2003).
A recent report indicated that an aldehyde reductase,
YqhD [Fig. 2(17)], is involved in protecting E. coli against
lipid peroxidation caused by the oxidative stress elicitors
2009 Federation of European Microbiological Societies
Published by Blackwell Publishing Ltd. All rights reserved
c
826
paraquat, H2O2, chromate or TeO23 , and that this enzyme
may be part of a glutathione-independent antioxidant
system (Pérez et al., 2008). Thus, at least in P. pseudoalcaligenes KF707 and in E. coli K-12, TeO23 toxic effects seem to
be directly related to increased intracellular ROS as well as a
decrease in the cellular thiol content (Pérez et al., 2007;
Tremaroli et al., 2007).
In this context, two main mechanisms controlling the
cytoplasmatic redox balance appear to be directly affected by
TeO23 . These are the glutathione–glutaredoxin and the
thioredoxin systems (Holmgren, 1989; Carmel-Harel &
Storz, 2000). The tripeptide glutathione (L-g-glutamyl-cysteinyl-glycine) and thioredoxin (12 kDa) act as general
reducers in the cell’s cytoplasm (Prinz et al., 1997; Smirnova
et al., 1999). GSH reduces intracellular disulfide bonds,
generally in conjunction with glutaredoxin (Carmel-Harel
& Storz, 2000). Being predominantly reduced, cytoplasmic
GSH (c. 5 mM) is thought to be the main controller of the
redox environment in the cytoplasm of E. coli (Aslund &
Beckwith, 1999). In turn, reduced glutathione levels are
controlled by glutathione reductase, which reduces oxidized
glutathione (GSSG) in an NADPH-dependent reaction. The
coenzyme is then recycled by glucose-6-phosphate dehydrogenase in the pentose phosphate pathway [Fig. 2(22)].
In spite of the numerous cell processes that involve
glutathione, including its role in defense against oxidative
stress (Carmel-Harel & Storz, 2000), it has been observed
that this molecule does not appear to be essential for E. coli
survival (Fuchs & Warner, 1975). In addition, and although
common in most Gram-negative bacteria, GSH has been
shown to be present in only a few Gram-positive microorganisms (Fahey et al., 1978).
Three glutaredoxins (1–3 encoded by grxA, grxB, and
grxC, respectively) and two thioredoxins (1 and 2, encoded
by trxA and trxC, respectively) have been described in E. coli.
Most glutaredoxins, all thioredoxins, and thioredoxin reductase (encoded by trxB) contain a conserved motif,
CXXC, at the active site. They also share similar structures
containing three a-helices and four-fiber b-sheets.
Escherichia coli mutations in GSH and glutaredoxin
systems have shown that thioredoxin 1 (TrxA), thioredoxin
2 (TrxC), and thioredoxin reductase (TrxB) are not essential
for the bacterium. trxA and trxB mutants, a phenotype that
was not observed with trxC cells (Takemoto et al., 1998; Ritz
et al., 2000), showed increased sensitivity to H2O2.
Albeit viable, E. coli lacking genes involved in GSH
biosynthesis such as gshA, gshB, and gorA (encoding glutathione synthetase isoenzymes and glutathione reductase,
respectively) are highly sensitive to the specific thiol oxidizer
diamide (Li et al., 2003). Under normal growth conditions,
these mutants exhibit a phenotype similar to that of the
parental strain. Similar results were observed for grxA and
grxC mutants (Aslund et al., 1994), suggesting an indepen2009 Federation of European Microbiological Societies
Published by Blackwell Publishing Ltd. All rights reserved
c
T.G. Chasteen et al.
dent requirement of these two systems to cope with oxidative stress under these culture conditions. In this context, the
GSH-dependent protective system is mainly observed in
Gram-negative bacteria, with the exception of Lactococcus
lactis and some Bacillus and Clostridium species (Fahey
et al., 1978; Zhang et al., 2007).
Double gsh/grx E. coli mutants revealed that the integrity
of at least one of these systems is required for aerobic growth
of this bacterium (Prinz et al., 1997). These mutants also
proved to be unable to reduce disulfide linkage in the
cytoplasm. Although these observations emphasize the importance of GSH in maintaining the cytoplasm’s reducing
atmosphere, the idea is that this kind of function would not
be represented exclusively by these reductants in bacteria.
This has prompted workers to pursue a continuous search of
alternative reducing systems that may involve other thiolcontaining molecules.
Sulfur and cysteine metabolism and
TeO23 tolerance
Living organisms require sulfur for the synthesis of proteins
and essential cofactors. Bacteria and plants acquire sulfur
through assimilation from inorganic sources such as sulfate
and thiosulfate, or from organic ones such as sulfate esters,
sulfamates, and sulfonates (Uria-Nickelsen et al., 1993).
One of the main products of sulfur assimilation is the
amino acid cysteine, which performs vital functions in
enzyme catalysis and in protein structure, among others.
For example, cysteine residues play a crucial role in [Fe–S]
cluster-containing proteins as cytochromes and dehydratases of intermediary metabolic pathways such as fumarases
and aconitases [Fig. 2(7)]. Important Cys residues have also
been described in E. coli Te resistance proteins TehA and
TehB. Replacement of these cysteines by alanine causes
decreased TeO23 resistance (Dyllick-Brenzinger et al., 2000).
Previous work with G. stearothermophilus and S. aureus
has pointed out the relevance of cysteine-metabolism-related genes and K2TeO3 resistance. Three genes coding for
proteins acting in sulfur assimilation or using cysteine as a
substrate have been identified in G. stearothermophilus:
cobA, encoding SUMT methyltransferase [Fig. 2(12)], an
enzyme that participates in the biosynthesis of siroheme, a
cofactor of sulfite reductase (Araya et al., 2009), cysK,
encoding cysteine synthase [Fig. 2(11)], which catalyzes the
last step in cysteine biosynthesis (Vásquez et al., 2001;
Saavedra et al., 2004), and iscS, specifying the IscS cysteine
desulfurase [Fig. 2(9)], which is involved, among other
functions, in the recovery and synthesis of [Fe–S] clustercontaining enzymes (Flint et al., 1996; Tantaleán et al.,
2003). Recent publications have shown the involvement of
cysK and cysM genes in K2TeO3 resistance as well as in
response to oxidative stress (Lithgow et al., 2004; Das et al.,
FEMS Microbiol Rev 33 (2009) 820–832
827
Toxicity of and bacterial resistance to tellurite
2005) and that cysK is differentially expressed in response to
H2O2, paraquat, and diamide (Pomposiello et al., 2001;
Leichert et al., 2003). Much earlier, cysK mutants of E. coli
had also been obtained from selenite-resistant mutants
(Fimmel & Loughlin, 1977).
It has long been argued that TeO23 toxicity could be a
consequence of its strong oxidant nature (Siliprandi et al.,
1971; O’Gara et al., 1997; Garberg et al., 1999; Taylor, 1999).
Exposure would eventually result in an oxidative stress
status in the cell. This last condition is associated with the
presence of ROS such as hydrogen peroxide, superoxide, and
hydroxyl radicals. In this context, intracellular enzymatic
TeO23 reduction by nitrate reductase (Avazeri et al., 1997),
dihydrolipoamide dehydrogenase [Castro et al., 2008; Fig.
2(4)], catalase, or by other enzymes [Fig. 2(2)] would result
in the generation of superoxide (Calderón et al., 2006; Pérez
et al., 2007). TeO23 could also be reduced chemically to
lower oxidation states by glutathione or by other reduced
thiol-containing molecules [Fig. 2(3)]. A direct consequence
of this reduction reaction would be a drastic decrease in the
concentration of antioxidant molecules such as glutathione
and cysteine, among others. Thus, it would be possible to
speculate that turning on the biosynthetic machinery of
cellular antioxidants would result in a phenotype of higher
TeO23 tolerance.
Recent research described a Gram-negative bacterium,
which, in part, responded to TeO23 by conversion to Te0,
which was found to be deposited in the cytoplasm (Pages
et al., 2008). This microorganism could grow in the presence
of 25 mM TeO23 and 50 mM selenite, another toxic oxyanion, which was also reduced and collected in the cell as a
precipitated metalloid. A survey of Gram-positive bacteria
and yeasts isolated from salt marsh sediments that were
TeO23 resistant produced reduced volatile organo-tellurides,
mostly dimethyl telluride, when amended with TeO23 . Some
strains, when exposed to metalloidal salts, exhibited intracellular elemental Te precipitates (Ollivier et al., 2008).
On the other hand, E. coli cells expressing defined G.
stearothermophilus genes (cloned in low copy number plasmids along with their own promoters) exhibit increased
tolerance to potassium tellurite and to some oxidative stress
elicitors along with some protection against the poisonous
effect of diamide, a general thiol oxidizer (Fuentes et al.,
2007). Similar results were previously reported when the
Bacillus subtilis gene expression profile was analyzed after
growing in the presence of hydrogen peroxide (Leichert
et al., 2003). More recently, it was shown that TeO23
activates superoxide dismutase in P. pseudoalcaligenes (Tremaroli et al., 2007) and appears to induce the expression of
some genes of the OxyR and SoxR regulons of E. coli (Pérez
et al., 2007). Moreover, it was shown that TeO23 positively
regulates gutS and the genes of the terZABCDE operon in
E. coli and P. mirabilis, respectively (Guzzo & Dubow, 2000;
FEMS Microbiol Rev 33 (2009) 820–832
Toptchieva et al., 2003). The presence of sequences similar to
the OxyR-binding motifs in the operon of P. mirabilis
suggests that its induction by TeO23 would be dependent
on this transcriptional regulator.
Finally, most genes belonging to the E. coli Cys regulon
were shown to be induced in the presence of potassium
tellurite, even though cysB and cysE expression was repressed
when cells were grown in rich media (Fuentes et al., 2007).
In this context, E. coli strains lacking genes involved in
cysteine biosynthesis exhibit an increased sensitivity to
K2TeO3 (C. Vásquez, unpublished data), suggesting that
most components of cysteine metabolism are required to
cope with the stress caused by TeO23 . These results show
that cysteine-metabolism-related genes are induced upon
TeO23 exposure and that cysteine, sulfide, or thiosulfate
repression is probably due to a strong intracellular reduction
of reduced thiols. Thus, a direct relationship between
cysteine biosynthesis and TeO23 tolerance can be established
in both Gram-negative (E. coli) and Gram-positive
(G. stearothermophilus) bacteria. In support of this, recent
evidence by Tremaroli et al. (2009) showed that high TeO23
resistance in P. pseudoalcaligenes KF707 can be correlated
with a reconfiguration of the cellular metabolism as well as
with an induced oxidative stress response.
Concluding remarks
Although a necessary biochemical role for Te has not been
established as it has for Se, it is not unreasonable to assume
that ultimately Te will be found to be a necessary trace
metalloid for some organisms.
Although the reduction and methylation mechanism has
not yet been determined, the production of insoluble Te
appears to be a common means of partially detoxifying
much more damaging and highly oxidative Te oxyanions.
Why is TeO23 so toxic? What are tellurite’s main intracellular targets? What other thiol pool in addition to GSH, if
any, is depleted upon TeO23 exposure? Why does the cell
assume the apparently unnecessary risk of superoxide generation upon TeO23 reduction? What is the ultimate mechanism underlying TeO23 resistance/toxicity?
In spite of the fact that progress in the field is slow and
more effort is needed, the answer to these intriguing
questions in the near future will help us to better comprehend the complex phenomena of TeO23 toxicity and bacterial TeO23 resistance.
Acknowledgements
The authors would like to thank Dr Simon Silver (University
of Illinois, Chicago) for critically reading the manuscript.
This work received financial support from Fondecyt grant #
1060022 and Dicyt-USACH to C.C.V. and from the Robert
2009 Federation of European Microbiological Societies
Published by Blackwell Publishing Ltd. All rights reserved
c
828
A. Welch Foundation (X-011) at Sam Houston State University to T.G.C.
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