Bacteria employ diverse mechanisms to manage toxic copper in their environments, and these evolutionary strategies can be divided into two main categories: accumulation and rationalization of metabolic pathways. The strategies employed depend on the bacteria's lifestyle and environmental context, optimizing the metabolic cost-benefit ratio. Environmental and opportunistically pathogenic bacteria often possess an extensive range of copper regulation systems in order to respond to variations in copper concentrations and environmental conditions, investing in diversity and/or redundancy as a safeguard against uncertainty. In contrast, obligate symbiotic bacteria, such as Neisseria gonorrhoeae and Bordetella pertussis, tend to have specialized and more parsimonious copper regulation systems designed to function in the relatively stable host environment. These evolutionary strategies maintain copper homeostasis even in challenging conditions like encounters within phagocytic cells. These examples highlight the adaptability of bacterial copper management systems, tailored to their specific lifestyles and environmental requirements, in the context of an evolutionary the trade-off between benefits and energy costs.

Since the emergence of life on Earth, metals have played a vital role in numerous biological processes. Iron was initially favored by bacteria due to its bioavailability [1], but ∼2.7 billion years ago, the increased presence of oxygen [2], triggered by the emergence of photosynthetic organisms, brought about a significant change [3]. This led to the oxidation of soluble iron into an insoluble form, limiting its availability, setting the stage for other metals soluble in their oxidized state, including copper, and the evolution of numerous diverse metal-based metabolic processes which have become crucial.

Copper is utilized by numerous enzymes involved in various essential metabolic pathways, such as electron transport [4,5], nitrogen metabolism [6,7], degradation of aromatic compounds [8], and oxygen-related reactions. It also plays a critical role in the cytochromes c oxidase of the respiratory chain [9,10], thus contributing to the generation of the proton motive force, the energy source of ATP synthase [11]. However, the evolutionary adoption of copper came with concomitant toxic metabolites. Copper can induce oxidative stress (reactive oxygen species, ROS) by generating highly reactive hydroxyl radicals (OH˙) through the Fenton-like reaction [12–15]. These OH˙ radicals react swiftly with surrounding molecules including proteins, lipids, and nucleotides. Copper is directly or indirectly responsible for other stresses. It is responsible for the formation of reactive nitrogen species (RNS) [14,16]. It can also displace other metals complexed within proteins, leading to their malfunction, particularly in proteins containing iron-sulfur clusters [17]. Finally, copper can also disrupt protein folding [18] and induce disulfide bridge formation [19,20], both of which may impair protein functions, leading to cellular toxicity.

In the environment, some organisms such as amebae, have exploited the toxic properties of metals, particularly copper, for preying on bacteria through phagocytosis. One such mechanism that allows them to subsequently kill their prey is metal poisoning [21]. Phagocytosis is deeply conserved throughout the evolutionary of eukaryotes and has become a crucial component of the immune system of metazoans, including humans. Inflammatory cascades trigger the import of copper in phagocytic cells into phagolysosomes to kill bacteria [22,23]. In the case of humans, the transporter Ctr1 facilitates the import of copper from the extracellular environment [24], which is then managed by the chaperone Atox1 [25,26]. Atox1, in turn, transfers the metal to ATPase ATP7A, which exports cytoplasmic copper into the phagolysosome [22,27]. This metal intoxication works synergistically with other bactericidal factors such as ROS [28,29], RNS [30,31], and indirectly, reactive carbonyl species (RCS) [32–35].

Prokaryotic organisms interacting with phagocytic cells have evolved and refined through natural selection strategies for copper detection, tolerance, defense, and detoxification [36] (Figure 1). Yet certain fundamental metabolic processes, like low molecular mass thiols such as glutathione, ubiquitous in all organisms, aid in maintaining cytoplasmic redox balance and limiting copper ion state transitions and their effects [37–39]. Among well studied bacteria, various lifestyles and copper homeostasis strategies have been observed. Bacteria capable of living both free in the environment and inside a host have accumulated a diversity of copper defense mechanisms, some of which exhibit partial redundancy. These mechanisms include systems such as HME-type RND (e.g. CusABC), multicopper oxidases, ATPases, and chelation mechanisms [40]. For example, Pseudomonas aeruginosa possesses, in addition to CusABC and PcoAB systems, two independently regulated CopA-type ATPases and two distinct CopZ-type chaperones [41,42]. These different systems are finely regulated by two regulators, CopRS [43], which senses periplasmic copper, and CueR, which senses cytoplasmic copper [41]. Indirect defense mechanisms are also present in P. aeruginosa, such as the secretion of pyoverdine and pyochelin, which reduce the toxicity of various metals [44]. Additionally, the repression of copper import proteins like OprC has been observed [45,46]. Other organisms, including Staphylococcus aureus, even have mobile genetic elements carrying copper resistance operons, similar to those observed in the context of antibiotic resistance [47,48]. Salmonella enterica serovar Typhimurium survives in various environments including the phagolysosome before invading macrophages. This bacterium has two copper ATPases, and a multicopper oxidase CueO (also known as CuiD), but unlike other Enterobacteriaceae, S. enterica lacks a CusABC-type copper export system [49]. Rather, it has evolved a chelation-based detoxification strategy, involving copper chaperones GolB [50], Csp3 [51], and especially CueP [49,52]. CueP is a periplasmic copper chaperone that largely compensates for the loss of CusABC in terms of copper tolerance [49]. CueP and CusABC appear to have a similar role in metal resistance in vitro. However, CueP is more effective in the context of surviving phagocytosis [49]. Despite the accumulation of copper homeostasis systems, some of which are redundant, S. enterica appears to have opted for the rationalization of one of these systems by replacing the complex CusABC system with a sole chaperone, CueP. Additionally, S. enterica produces and secretes yersiniabactin, a siderophore capable of chelating excess copper the environment [53] and, in the context of an infection, acting as virulence-associated superoxide dismutase mimic [54]. These bacteria have accumulated specific copper defense mechanisms to cope with a range of stresses. In contrast with these examples, there are bacterial genera with an extremely restricted environmental niche. For example, Neisseria and Bordetella pertussis live almost exclusively on their host's mucosa [55,56]. This highly specific lifestyle appears to be associated with a reduced and optimized genome content which includes specific adaptations for copper homeostasis.

The majority of Neisseria species are obligate symbionts that predominantly colonize mucosae of mammalian hosts [57]. Among them, Neisseria meningitidis [58] and Neisseria gonorrhoeae [59] have been extensively studied due to their pathogenic potential. These bacteria primarily adopt a mucosal-associated extracellular lifestyle with limited intracellular survival capabilities [56]. Analysis of the N. gonorrhoeae genome suggests a minimalist copper homeostasis system. This bacterium possesses only the copper chaperone CopZ and the ATPase CopA [40]. Interestingly, this bacterium lacks of the CueR regulator [60], which typically controls the expression of the copA and copZ genes in gram negative bacteria. Instead, the ATPase is part of a regulon of four genes under the control of the NmlR regulator [60,61]. Comparative genomics suggests that this system is conserved in pathogenic Neisseria [62,63]. NmlR is present in several other pathogenic bacteria that colonize the mucosae of their hosts, such as Haemophilus influenzae [32,35] and Streptococcus pneumoniae [64]. NmlR is involved in regulating the response to ROS, RNS, and/or RCS, depending on the organism. In the case of N. gonorrhoeae, this regulator appears to respond to RNS. NmlR controls the expression of genes including adhC [65–67], estD [67,68], trxB [69], and the copA ATPase gene. Djoko et al. [60], who described this unique regulatory mechanism, demonstrated a deficiency in intracellular survival in the CopA ATPase mutant. They suggested that this NmlR regulon, which detoxifies RNS, ROS, and copper, is beneficial for survival during phagocytosis, as these three stressors have bactericidal properties. It appears that evolution has led to a rationalization of copper homeostasis mechanisms to cope with specific stresses (Figure 1).

Copper defense mechanisms and adaptations to copper-related stress induced by phagocytic cells.

Figure 1.
Copper defense mechanisms and adaptations to copper-related stress induced by phagocytic cells.

These cells, such as macrophages and neutrophils, generate various forms of stress using copper in the phagolysosome to kill engulfed bacteria. (1) The Ctr1 transporter imports copper into the cytosol, and then the Atox1 chaperone transfers it to ATP7A at the phagolysosome membrane for export into the lumen. (2) NADPH oxidase (NOX2) uses the electron potential of NADPH to produce O2.− in the phagolysosome lumen. This superoxide anion allows the formation of hydrogen peroxide and certain RNS. Myeloperoxidase produces HOCl using H2O2. (3) Inducible nitric oxide synthase (iNOS) produces nitric oxide, which leads to various RNS. RCS are produced indirectly by the reaction of ROS and RNS with the organic molecules of the bacterium. The diversity of copper management strategies is depicted in the lower panels. Some bacteria accumulate various homeostasis systems: (4) P. aeruginosa possesses two sensor systems, CopRS and CueR, which trigger the expression of disparate copper defense mechanisms. Furthermore, this bacterium can secrete certain molecules such as pyoverdine and pyochelin to buffer copper in the extracellular environment. Other bacteria accumulate redundant systems: (5) S. enterica has two closely related regulators, CueR and GolS, of the MerR-type; these regulators control the expression of ATPases and chaperones for copper export and detoxification by chelation. The synthesis and secretion of yersiniabactin also contributes to increased copper tolerance. In contrast, other bacteria exposed to different stresses have rationalized these mechanisms and retain only a minimalist system. (6) Pathogenic Neisseria detect reactive species (RS) through the NmlR regulator via disulfide bridge formation. This regulator induces the expression of three RS detoxification genes (adhC, estD, trxB) as well as that of the CopA ATPase copper exporter. (7) Bordetella pertussis detects excess copper via the CueR regulator, leading to the production of the CopZ protein capable of detoxifying copper by chelation, as well as two proteins (PrxGrx, GorB) for ROS detoxification utilizing a glutathione redox cycle (reduced: GSH, oxidized: GSSG). In both cases, a single signal triggers multiple responses. The red locii and the dotted arrows represent regulatory and metabolic pathways not detailed here but which play a role in copper tolerance.

Figure 1.
Copper defense mechanisms and adaptations to copper-related stress induced by phagocytic cells.

These cells, such as macrophages and neutrophils, generate various forms of stress using copper in the phagolysosome to kill engulfed bacteria. (1) The Ctr1 transporter imports copper into the cytosol, and then the Atox1 chaperone transfers it to ATP7A at the phagolysosome membrane for export into the lumen. (2) NADPH oxidase (NOX2) uses the electron potential of NADPH to produce O2.− in the phagolysosome lumen. This superoxide anion allows the formation of hydrogen peroxide and certain RNS. Myeloperoxidase produces HOCl using H2O2. (3) Inducible nitric oxide synthase (iNOS) produces nitric oxide, which leads to various RNS. RCS are produced indirectly by the reaction of ROS and RNS with the organic molecules of the bacterium. The diversity of copper management strategies is depicted in the lower panels. Some bacteria accumulate various homeostasis systems: (4) P. aeruginosa possesses two sensor systems, CopRS and CueR, which trigger the expression of disparate copper defense mechanisms. Furthermore, this bacterium can secrete certain molecules such as pyoverdine and pyochelin to buffer copper in the extracellular environment. Other bacteria accumulate redundant systems: (5) S. enterica has two closely related regulators, CueR and GolS, of the MerR-type; these regulators control the expression of ATPases and chaperones for copper export and detoxification by chelation. The synthesis and secretion of yersiniabactin also contributes to increased copper tolerance. In contrast, other bacteria exposed to different stresses have rationalized these mechanisms and retain only a minimalist system. (6) Pathogenic Neisseria detect reactive species (RS) through the NmlR regulator via disulfide bridge formation. This regulator induces the expression of three RS detoxification genes (adhC, estD, trxB) as well as that of the CopA ATPase copper exporter. (7) Bordetella pertussis detects excess copper via the CueR regulator, leading to the production of the CopZ protein capable of detoxifying copper by chelation, as well as two proteins (PrxGrx, GorB) for ROS detoxification utilizing a glutathione redox cycle (reduced: GSH, oxidized: GSSG). In both cases, a single signal triggers multiple responses. The red locii and the dotted arrows represent regulatory and metabolic pathways not detailed here but which play a role in copper tolerance.

Close modal

The Bordetella genus serves as a model system for studying the evolution of copper homeostasis despite the fact that most Bordetella species lack copper defense systems such as CusABC [40,70]. This genus includes bacteria adapted to various environments, with some closely associated with their hosts [71]. For instance, Bordetella bronchiseptica can cause respiratory infections in mammals but is able to survive outside the host and resist phagocytosis by both amebas and macrophages [72,73]. Conversely, Bordetella pertussis, an obligate symbiont armed with multiple virulence factors, lives primarily on the surface of the human respiratory epithelium [55,74] and has lost many non-essential metabolic pathways [75], including those related to copper [40,76] (Figure 1).

Although B. bronchiseptica and B. pertussis share several genes related to copper homeostasis, but transcriptomic analyses have revealed that copper defense systems CopI-PcoA-PcoB and CopA are inactive in B. pertussis [76]. This bacterium has evolved by deleting portions of its genome and disrupting genes through sequence insertions, particularly IS481, present in several dozen copies [75,77,78]. This evolutionary scenario suggests an ongoing genomic reduction of copper homeostasis systems in B. pertussis, as the bacterium is no longer exposed to copper-related stress in the environment and has only retained and refined mechanisms to evade copper-utilizing phagocytic cells [79,80], the last remaining source of copper stress in its niche.

While B. pertussis has reduced its copper defense arsenal [40], transcriptomic studies have identified a single remaining system regulated by the copper-sensitive regulator CueR. This system consists of the chaperone CopZ and two proteins involved in detoxifying oxidative stress, a glutathione-dependent peroxidase, and a glutathione reductase [76]. Although the ATPase CopA exporter is inactive due to a sequence insertion, CopZ plays a role in passive detoxification by binding free copper. Even though the other two proteins are not traditionally involved in copper tolerance, they benefit from a more wider dynamic range of regulation through the CueR regulator [76]. This system is specific to situations where copper is present in significant quantities, such as in the phagosome of macrophages, presumably exploiting the fact that in this context, ROS are also used as bactericidal factors [22]. Deletion mutants of this system show a significant decrease in survival after phagocytosis [76]. Outside of these conditions the system is repressed, thus avoiding unnecessary energy expenditure through the synthesis of non-essential proteins during the extracellular multiplication of B. pertussis on respiratory mucosa [23,36]. It is interesting to note that the repression of copper importation mechanisms also plays a role in metal tolerance in B. pertussis. This bacterium does not secrete siderophores/chalcophores capable of buffering copper but possesses a complex regulatory mechanism, using the CruR protein, leading to strong repression of the TonB-dependent transporter BfrG, hypothesized to be involved in copper import [81]. Therefore, this bacterium has rationalized its copper homeostasis mechanisms by losing non-essential genes and merging the remaining regulon with an oxidative stress defense mechanism (ROS).

The evolution of copper homeostasis mechanisms is directly linked to the lifestyle of bacteria. The strength of this relationship is even more pronounced at the host–bacteria interface. Free-living generalist bacteria subjected to environmental stresses have evolved an accumulation of a diverse and/or redundant set of systems to cope with varying conditions. In contrast, specialist bacteria exploiting narrow niches will rationalize their homeostasis mechanisms to both reduce diversity and redundancy to optimize the benefit-to-cost ratio.

The authors declare that there are no competing interests associated with the manuscript.

The figure was created with the assistance of Biorender.com.

RCS

reactive carbonyl species

RNS

reactive nitrogen species

ROS

reactive oxygen species

1
Crichton
,
R.R.
and
Pierre
,
J.-L.
(
2001
)
Old iron, young copper: from Mars to Venus
.
Biometals
14
,
99
112
2
Sessions
,
A.L.
,
Doughty
,
D.M.
,
Welander
,
P.V.
,
Summons
,
R.E.
and
Newman
,
D.K.
(
2009
)
The continuing puzzle of the great oxidation event
.
Curr. Biol.
19
,
R567
R574
3
Schirrmeister
,
B.E.
,
Gugger
,
M.
and
Donoghue
,
P.C.J.
(
2015
)
Cyanobacteria and the great oxidation event: evidence from genes and fossils
.
Palaeontology
58
,
769
785
4
Cahyono
,
R.N.
,
Yamanaka
,
M.
,
Nagao
,
S.
,
Shibata
,
N.
,
Higuchi
,
Y.
and
Hirota
,
S.
(
2020
)
3D domain swapping of azurin from Alcaligenes xylosoxidans
.
Metallomics
12
,
337
345
5
Scheiber
,
I.F.
,
Pilátová
,
J.
,
Malych
,
R.
,
Kotabova
,
E.
,
Krijt
,
M.
,
Vyoral
,
D.
et al (
2019
)
Copper and iron metabolism in Ostreococcus tauri – the role of phytotransferrin, plastocyanin and a chloroplast copper-transporting ATPase
.
Metallomics
11
,
1657
1666
6
Barreiro
,
D.S.
,
Oliveira
,
R.N.S.
and
Pauleta
,
S.R.
(
2023
)
Biochemical characterization of the copper nitrite reductase from Neisseria gonorrhoeae
.
Biomolecules
13
,
1215
7
Hein
,
S.
,
Simon
,
J
. (
2019
) Chapter four - bacterial nitrous oxide respiration: electron transport chains and copper transfer reactions. In
Advances in Microbial Physiology
(
Poole
,
R.K.
, ed.), pp.
137
175
,
Academic Press
. (Advances in Microbial Physiology; vol. 75)
,
The University of Sheffield, Firth Court, Western Bank, Sheffield, UK
.
8
Janusz
,
G.
,
Pawlik
,
A.
,
Świderska-Burek
,
U.
,
Polak
,
J.
,
Sulej
,
J.
,
Jarosz-Wilkołazka
,
A.
et al (
2020
)
Laccase properties, physiological functions, and evolution
.
Int. J. Mol. Sci.
21
,
966
9
Andrei
,
A.
,
Di Renzo
,
M.A.
,
Öztürk
,
Y.
,
Meisner
,
A.
,
Daum
,
N.
,
Frank
,
F.
et al (
2021
)
The CopA2-Type P1B-Type ATPase CcoI serves as central Hub for cbb3-type cytochrome oxidase biogenesis
.
Front. Microbiol.
12
,
712465
10
Marckmann
,
D.
,
Trasnea
,
P.-I.
,
Schimpf
,
J.
,
Winterstein
,
C.
,
Andrei
,
A.
,
Schmollinger
,
S.
et al (
2019
)
The cbb3-type cytochrome oxidase assembly factor CcoG is a widely distributed cupric reductase
.
Proc. Natl Acad. Sci. U.S.A.
116
,
21166
21175
11
Lee
,
H.J.
,
Reimann
,
J.
,
Huang
,
Y.
and
Ädelroth
,
P.
(
2012
)
Functional proton transfer pathways in the heme–copper oxidase superfamily
.
Biochim. Biophys. Acta
1817
,
537
544
12
Dalecki,
A.G.
,
Crawford,
C.L.
,
Wolschendorf
,
F
. (
2017
) Chapter six - copper and antibiotics: discovery, modes of action, and opportunities for medicinal applications. In
Advances in Microbial Physiology
(
Poole
,
R.K.
, ed.), pp.
193
260
,
Academic Press
.
(Microbiology of Metal Ions; vol. 70)
,
The University of Sheffield, Firth Court, Western Bank, Sheffield, UK
.
13
Solioz
,
M
. (
2018
) Copper homeostasis in gram-negative bacteria. In
Copper and Bacteria: Evolution, Homeostasis and Toxicity
(
Solioz
,
M.
, ed.), pp.
49
80
,
Springer International Publishing
,
Cham
(SpringerBriefs in Molecular Science). https://doi.org/10.1007/978-3-319-94439-5_4
14
Husain
,
N.
and
Mahmood
,
R.
(
2019
)
Copper(II) generates ROS and RNS, impairs antioxidant system and damages membrane and DNA in human blood cells
.
Environ. Sci. Pollut. Res.
26
,
20654
20668
15
Pham
,
A.N.
,
Xing
,
G.
,
Miller
,
C.J.
and
Waite
,
T.D.
(
2013
)
Fenton-like copper redox chemistry revisited: hydrogen peroxide and superoxide mediation of copper-catalyzed oxidant production
.
J. Catal.
301
,
54
64
16
Fang
,
F.C.
and
Vázquez-Torres
,
A.
(
2019
)
Reactive nitrogen species in host–bacterial interactions
.
Curr. Opin. Immunol.
60
,
96
102
17
Macomber
,
L.
and
Imlay
,
J.A.
(
2009
)
The iron-sulfur clusters of dehydratases are primary intracellular targets of copper toxicity
.
Proc. Natl Acad. Sci. U.S.A.
106
,
8344
8349
18
Zuily
,
L.
,
Lahrach
,
N.
,
Fassler
,
R.
,
Genest
,
O.
,
Faller
,
P.
,
Sénèque
,
O.
et al (
2022
)
Copper induces protein aggregation, a toxic process compensated by molecular chaperones
.
mBio
13
,
e03251-21
19
Hiniker
,
A.
,
Collet
,
J.-F.
and
Bardwell
,
J.C.A.
(
2005
)
Copper stress causes an in vivo requirement for the Escherichia coli disulfide isomerase DsbC
.
J. Biol. Chem.
280
,
33785
33791
20
Durand
,
A.
,
Azzouzi
,
A.
,
Bourbon
,
M.-L.
,
Steunou
,
A.-S.
,
Liotenberg
,
S.
,
Maeshima
,
A.
et al (
2015
)
c-Type cytochrome assembly is a key target of copper toxicity within the bacterial periplasm
.
mBio
6
,
10.1128/mbio.01007-15
21
Hao
,
X.
,
Lüthje
,
F.
,
Rønn
,
R.
,
German
,
N.A.
,
Li
,
X.
,
Huang
,
F.
et al (
2016
)
A role for copper in protozoan grazing – two billion years selecting for bacterial copper resistance
.
Mol. Microbiol.
102
,
628
641
22
White
,
C.
,
Lee
,
J.
,
Kambe
,
T.
,
Fritsche
,
K.
and
Petris
,
M.J.
(
2009
)
A role for the ATP7A copper-transporting ATPase in macrophage bactericidal activity
.
J. Biol. Chem.
284
,
33949
33956
23
Sheldon
,
J.R.
and
Skaar
,
E.P.
(
2019
)
Metals as phagocyte antimicrobial effectors
.
Curr. Opin. Immunol.
60
,
1
9
24
Ren
,
F.
,
Logeman
,
B.L.
,
Zhang
,
X.
,
Liu
,
Y.
,
Thiele
,
D.J.
and
Yuan
,
P.
(
2019
)
X-ray structures of the high-affinity copper transporter Ctr1
.
Nat. Commun.
10
,
1386
25
Hatori
,
Y.
and
Lutsenko
,
S.
(
2016
)
The role of copper chaperone Atox1 in coupling redox homeostasis to intracellular copper distribution
.
Antioxidants
5
,
25
26
Hatori
,
Y.
,
Inouye
,
S.
and
Akagi
,
R.
(
2017
)
Thiol-based copper handling by the copper chaperone Atox1
.
IUBMB Life
69
,
246
254
27
Lutsenko
,
S.
(
2021
)
Dynamic and cell-specific transport networks for intracellular copper ions
.
J. Cell Sci.
134
,
jcs240523
28
Herb
,
M.
and
Schramm
,
M.
(
2021
)
Functions of ROS in macrophages and antimicrobial immunity
.
Antioxidants
10
,
313
29
Zhang
,
X.-W.
,
Oleinick
,
A.
,
Jiang
,
H.
,
Liao
,
Q.-L.
,
Qiu
,
Q.-F.
,
Svir
,
I.
et al (
2019
)
Electrochemical monitoring of ROS/RNS homeostasis within individual phagolysosomes inside single macrophages
.
Ang. Chem.
131
,
7835
7838
30
Vazquez-Torres
,
A.
,
Xu
,
Y.
,
Jones-Carson
,
J.
,
Holden
,
D.W.
,
Lucia
,
S.M.
,
Dinauer
,
M.C.
et al (
2000
)
Salmonella pathogenicity Island 2-dependent evasion of the phagocyte NADPH oxidase
.
Science
287
,
1655
1658
31
Davis
,
A.S.
,
Vergne
,
I.
,
Master
,
S.S.
,
Kyei
,
G.B.
,
Chua
,
J.
and
Deretic
,
V.
(
2007
)
Mechanism of inducible nitric oxide synthase exclusion from mycobacterial phagosomes
.
PLOS Pathog.
3
,
e186
32
Kidd
,
S.P.
,
Jiang
,
D.
,
Tikhomirova
,
A.
,
Jennings
,
M.P.
and
McEwan
,
A.G.
(
2012
)
A glutathione-based system for defense against carbonyl stress in Haemophilus influenzae
.
BMC Microbiol.
12
,
159
33
Anderson
,
M.M.
,
Hazen
,
S.L.
,
Hsu
,
F.F.
and
Heinecke
,
J.W.
(
1997
)
Human neutrophils employ the myeloperoxidase-hydrogen peroxide-chloride system to convert hydroxy-amino acids into glycolaldehyde, 2-hydroxypropanal, and acrolein. A mechanism for the generation of highly reactive alpha-hydroxy and alpha,beta-unsaturated aldehydes by phagocytes at sites of inflammation
.
J. Clin. Invest.
99
,
424
432
34
Okado-Matsumoto
,
A.
and
Fridovich
,
I.
(
2000
)
The role of α,β-dicarbonyl compounds in the toxicity of short chain sugars
.
J. Biol. Chem.
275
,
34853
34857
35
Chen
,
N.H.
,
Djoko
,
K.Y.
,
Veyrier
,
F.J.
and
McEwan
,
A.G.
(
2016
)
Formaldehyde stress responses in bacterial pathogens
.
Front. Microbiol.
7
,
257
36
Focarelli
,
F.
,
Giachino
,
A.
and
Waldron
,
K.J.
(
2022
)
Copper microenvironments in the human body define patterns of copper adaptation in pathogenic bacteria
.
PLOS Pathog.
18
,
e1010617
37
Bhattacharjee
,
A.
,
Chakraborty
,
K.
and
Shukla
,
A.
(
2017
)
Cellular copper homeostasis: current concepts on its interplay with glutathione homeostasis and its implication in physiology and human diseases
.
Metallomics
9
,
1376
1388
38
Helbig
,
K.
,
Bleuel
,
C.
,
Krauss
,
G.J.
and
Nies
,
D.H.
(
2008
)
Glutathione and transition-metal homeostasis in Escherichia coli
.
J. Bacteriol.
190
,
5431
5438
39
Stewart
,
L.J.
,
Ong
,
C.Y.
,
Zhang
,
M.M.
,
Brouwer
,
S.
,
McIntyre
,
L.
,
Davies
,
M.R.
et al (
2020
)
Role of glutathione in buffering excess intracellular copper in Streptococcus pyogenes
.
mBio
11
,
10.1128/mbio.02804-20
40
Antoine
,
R.
,
Rivera-Millot
,
A.
,
Roy
,
G.
and
Jacob-Dubuisson
,
F.
(
2019
)
Relationships between copper-related proteomes and lifestyles in β proteobacteria
.
Front. Microbiol.
10
,
2217
41
Quintana
,
J.
,
Novoa-Aponte
,
L.
and
Argüello
,
J.M.
(
2017
)
Copper homeostasis networks in the bacterium Pseudomonas aeruginosa
.
J. Biol. Chem.
292
,
15691
15704
42
Novoa-Aponte
,
L.
,
Ramírez
,
D.
and
Argüello
,
J.M.
(
2019
)
The interplay of the metallosensor CueR with two distinct CopZ chaperones defines copper homeostasis in Pseudomonas aeruginosa
.
J. Biol. Chem.
294
,
4934
4945
43
Novoa-Aponte
,
L.
,
Xu
,
C.
,
Soncini
,
F.C.
and
Argüello
,
J.M.
(
2020
)
The Two-component system CopRS maintains subfemtomolar levels of free copper in the periplasm of Pseudomonas aeruginosa using a phosphatase-based mechanism
.
mSphere
5
,
10.1128/msphere.01193-20
44
Braud
,
A.
,
Geoffroy
,
V.
,
Hoegy
,
F.
,
Mislin
,
G.L.A.
and
Schalk
,
I.J.
(
2010
)
Presence of the siderophores pyoverdine and pyochelin in the extracellular medium reduces toxic metal accumulation in Pseudomonas aeruginosa and increases bacterial metal tolerance
.
Environ. Microbiol. Rep.
2
,
419
425
45
Han
,
Y.
,
Wang
,
T.
,
Chen
,
G.
,
Pu
,
Q.
,
Liu
,
Q.
,
Zhang
,
Y.
et al (
2019
)
A Pseudomonas aeruginosa type VI secretion system regulated by CueR facilitates copper acquisition
.
PLOS Pathog.
15
,
e1008198
46
Bhamidimarri
,
S.P.
,
Young
,
T.R.
,
Shanmugam
,
M.
,
Soderholm
,
S.
,
Baslé
,
A.
,
Bumann
,
D.
et al (
2021
)
Acquisition of ionic copper by the bacterial outer membrane protein OprC through a novel binding site
.
PLOS Biol.
19
,
e3001446
47
Rosario-Cruz
,
Z.
,
Eletsky
,
A.
,
Daigham
,
N.S.
,
Al-Tameemi
,
H.
,
Swapna
,
G.V.T.
,
Kahn
,
P.C.
et al (
2019
)
The copBL operon protects Staphylococcus aureus from copper toxicity: CopL is an extracellular membrane–associated copper-binding protein
.
J. Biol. Chem.
294
,
4027
4044
48
Purves
,
J.
,
Thomas
,
J.
,
Riboldi
,
G.P.
,
Zapotoczna
,
M.
,
Tarrant
,
E.
,
Andrew
,
P.W.
et al (
2018
)
A horizontally gene transferred copper resistance locus confers hyper-resistance to antibacterial copper toxicity and enables survival of community acquired methicillin resistant Staphylococcus aureus USA300 in macrophages
.
Environ. Microbiol.
20
,
1576
1589
49
Méndez
,
A.A.E.
,
Mendoza
,
J.I.
,
Echarren
,
M.L.
,
Terán
,
I.
,
Checa
,
S.K.
and
Soncini
,
F.C.
(
2022
)
Evolution of copper homeostasis and virulence in Salmonella
.
Front. Microbiol.
13
,
823176
50
Espariz
,
M.
,
Checa
,
S.K.
,
Audero
,
M.E.P.
,
Pontel
,
L.B.
and
Soncini
,
F.C.
(
2007
)
Dissecting the Salmonella response to copper
.
Microbiology
153
,
2989
2997
51
Dennison
,
C.
,
David
,
S.
and
Lee
,
J.
(
2018
)
Bacterial copper storage proteins
.
J. Biol. Chem.
293
,
4616
4627
52
Subedi
,
P.
,
Paxman
,
J.J.
,
Wang
,
G.
,
Ukuwela
,
A.A.
,
Xiao
,
Z.
and
Heras
,
B.
(
2019
)
The Scs disulfide reductase system cooperates with the metallochaperone CueP in Salmonella copper resistance
.
J. Biol. Chem.
294
,
15876
15888
53
Chaturvedi
,
K.S.
,
Hung
,
C.S.
,
Crowley
,
J.R.
,
Stapleton
,
A.E.
and
Henderson
,
J.P.
(
2012
)
The siderophore yersiniabactin binds copper to protect pathogens during infection
.
Nat. Chem. Biol.
8
,
731
736
54
Chaturvedi
,
K.S.
,
Hung
,
C.S.
,
Giblin
,
D.E.
,
Urushidani
,
S.
,
Austin
,
A.M.
,
Dinauer
,
M.C.
et al (
2014
)
Cupric yersiniabactin is a virulence-associated superoxide dismutase mimic
.
ACS Chem. Biol.
9
,
551
561
55
Solans
,
L.
and
Locht
,
C.
(
2019
)
The role of mucosal immunity in pertussis
.
Front. Immunol.
9
,
3068
56
Mikucki
,
A.
,
McCluskey
,
N.R.
and
Kahler
,
C.M.
(
2022
)
The host-pathogen interactions and epicellular lifestyle of Neisseria meningitidis
.
Front. Cell. Infect. Microbiol.
12
,
862935
57
Diallo
,
K.
,
MacLennan
,
J.
,
Harrison
,
O.B.
,
Msefula
,
C.
,
Sow
,
S.O.
,
Daugla
,
D.M.
et al (
2019
)
Genomic characterization of novel Neisseria species
.
Sci. Rep.
9
,
13742
58
Caugant
,
D.A.
and
Brynildsrud
,
O.B.
(
2020
)
Neisseria meningitidis: using genomics to understand diversity, evolution and pathogenesis
.
Nat. Rev. Microbiol.
18
,
84
96
59
Walker
,
E.
,
van Niekerk
,
S.
,
Hanning
,
K.
,
Kelton
,
W.
and
Hicks
,
J.
(
2023
)
Mechanisms of host manipulation by Neisseria gonorrhoeae
.
Front. Microbiol.
14
,
1119834
60
Djoko
,
K.Y.
,
Franiek
,
J.A.
,
Edwards
,
J.L.
,
Falsetta
,
M.L.
,
Kidd
,
S.P.
,
Potter
,
A.J.
et al (
2012
)
Phenotypic characterization of a copA mutant of Neisseria gonorrhoeae identifies a link between copper and nitrosative stress
.
Infect. Immun.
80
,
1065
1071
61
Kidd
,
S.P.
,
Potter
,
A.J.
,
Apicella
,
M.A.
,
Jennings
,
M.P.
and
McEwan
,
A.G.
(
2005
)
Nmlr of Neisseria gonorrhoeae: a novel redox responsive transcription factor from the MerR family
.
Mol. Microbiol.
57
,
1676
1689
62
Kidd
,
S.P.
(
2011
)
Novel regulation in response to host-generated stresses: the MerR family of regulators in pathogenic bacteria
.
Stress Response Pathog. Bact.
19
,
93
114
63
McEwan
,
A.G.
,
Djoko
,
K.Y.
,
Chen
,
N.H.
,
Couñago
,
R.L.M.
,
Kidd
,
S.P.
,
Potter
,
A.J.
et al. (
2011
) Chapter 1 - Novel Bacterial MerR-like regulators: their role in the response to carbonyl and nitrosative stress. In
Advances in Microbial Physiology
(
Poole
,
R.K.
, ed.), pp.
1
22
, vol. 58,
Academic Press
,
The University of Sheffield, Firth Court, Western Bank, Sheffield, UK
64
Fritsch
,
V.N.
,
Linzner
,
N.
,
Busche
,
T.
,
Said
,
N.
,
Weise
,
C.
,
Kalinowski
,
J.
et al (
2023
)
The MerR-family regulator NmlR is involved in the defense against oxidative stress in Streptococcus pneumoniae
.
Mol. Microbiol.
119
,
191
207
65
Kidd
,
S.P.
,
Jiang
,
D.
,
Jennings
,
M.P.
and
McEwan
,
A.G.
(
2007
)
Glutathione-dependent alcohol dehydrogenase AdhC Is required for defense against nitrosative stress in Haemophilus influenzae
.
Infect. Immun.
75
,
4506
4513
66
Potter
,
A.J.
,
Kidd
,
S.P.
,
Jennings
,
M.P.
and
McEwan
,
A.G.
(
2007
)
Evidence for distinctive mechanisms of S-nitrosoglutathione metabolism by AdhC in two closely related species, Neisseria gonorrhoeae and Neisseria meningitidis
.
Infect. Immun.
75
,
1534
1536
67
Chen
,
N.H.
,
Couñago
,
R.M.
,
Djoko
,
K.Y.
,
Jennings
,
M.P.
,
Apicella
,
M.A.
,
Kobe
,
B.
et al (
2013
)
A glutathione-dependent detoxification system is required for formaldehyde resistance and optimal survival of Neisseria meningitidis in biofilms
.
Antioxid. Redox Signal.
18
,
743
755
68
Potter
,
A.J.
,
Kidd
,
S.P.
,
Edwards
,
J.L.
,
Falsetta
,
M.L.
,
Apicella
,
M.A.
,
Jennings
,
M.P.
et al (
2009
)
Esterase D is essential for protection of Neisseria gonorrhoeae against nitrosative stress and for bacterial growth during interaction with cervical epithelial cells
.
J. Infect. Dis.
200
,
273
278
69
Potter
,
A.J.
,
Kidd
,
S.P.
,
Edwards
,
J.L.
,
Falsetta
,
M.L.
,
Apicella
,
M.A.
,
Jennings
,
M.P.
et al (
2009
)
Thioredoxin reductase is essential for protection of Neisseria gonorrhoeae against killing by nitric oxide and for bacterial growth during interaction with cervical epithelial cells
.
J. Infect. Dis.
199
,
227
235
70
Halder
,
U.
,
Biswas
,
R.
,
Kabiraj
,
A.
,
Deora
,
R.
,
Let
,
M.
,
Roy
,
R.K.
et al (
2022
)
Genomic, morphological, and biochemical analyses of a multi-metal resistant but multi-drug susceptible strain of Bordetella petrii from hospital soil
.
Sci. Rep.
12
,
8439
71
Soumana I
,
H.
,
Linz
,
B.
and
Harvill
,
E.T.
(
2017
)
Environmental origin of the genus bordetella
.
Front. Microbiol.
8
,
28
72
Ma
,
L.
,
Linz
,
B.
,
Caulfield
,
A.D.
,
Dewan
,
K.K.
,
Rivera
,
I.
and
Harvill
,
E.T.
(
2022
)
Natural history and ecology of interactions between bordetella species and amoeba
.
Front. Cell. Infect. Microbiol.
12
,
798317
73
Taylor-Mulneix
,
D.L.
,
Bendor
,
L.
,
Linz
,
B.
,
Rivera
,
I.
,
Ryman
,
V.E.
,
Dewan
,
K.K.
et al (
2017
)
Bordetella bronchiseptica exploits the complex life cycle of Dictyostelium discoideum as an amplifying transmission vector
.
PLOS Biol.
15
,
e2000420
74
Belcher
,
T.
,
Dubois
,
V.
,
Rivera-Millot
,
A.
,
Locht
,
C.
and
Jacob-Dubuisson
,
F.
(
2021
)
Pathogenicity and virulence of Bordetella pertussis and its adaptation to its strictly human host
.
Virulence
12
,
2608
2632
75
Parkhill
,
J.
,
Sebaihia
,
M.
,
Preston
,
A.
,
Murphy
,
L.D.
,
Thomson
,
N.
,
Harris
,
D.E.
et al (
2003
)
Comparative analysis of the genome sequences of Bordetella pertussis, Bordetella parapertussis and Bordetella bronchiseptica
.
Nat. Genet.
35
,
32
40
76
Rivera-Millot
,
A.
,
Slupek
,
S.
,
Chatagnon
,
J.
,
Roy
,
G.
,
Saliou
,
J.-M.
,
Billon
,
G.
et al (
2021
)
Streamlined copper defenses make Bordetella pertussis reliant on custom-made operon
.
Commun. Biol.
4
,
1
12
77
Diavatopoulos
,
D.A.
,
Cummings
,
C.A.
,
Schouls
,
L.M.
,
Brinig
,
M.M.
,
Relman
,
D.A.
and
Mooi
,
F.R.
(
2005
)
Bordetella pertussis, the causative agent of whooping cough, evolved from a distinct, human-associated lineage of B. bronchiseptica
.
PLOS Pathog.
1
,
e45
78
Siguier
,
P.
,
Gourbeyre
,
E.
and
Chandler
,
M.
(
2014
)
Bacterial insertion sequences: their genomic impact and diversity
.
FEMS Microbiol. Rev.
38
,
865
891
79
Gestal
,
M.C.
,
Howard
,
L.K.
,
Dewan
,
K.
,
Johnson
,
H.M.
,
Barbier
,
M.
,
Bryant
,
C.
et al (
2019
)
Enhancement of immune response against Bordetella spp. by disrupting immunomodulation
.
Sci. Rep.
9
,
20261
80
Andreasen
,
C.
and
Carbonetti
,
N.H.
(
2008
)
Pertussis toxin inhibits early chemokine production to delay neutrophil recruitment in response to Bordetella pertussis respiratory tract infection in mice
.
Infect. Immun.
76
,
5139
5148
81
Roy
,
G.
,
Antoine
,
R.
,
Schwartz
,
A.
,
Slupek
,
S.
,
Rivera-Millot
,
A.
,
Boudvillain
,
M.
et al (
2022
)
Posttranscriptional regulation by copper with a new upstream open reading frame
.
mBio
13
,
e00912-22
This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and the Royal Society of Biology and distributed under the Creative Commons Attribution License 4.0 (CC BY).