Karrera Y. Djoko's research while affiliated with Durham University and other places

Publications (48)

Article
Full-text available
All bacteria possess homeostastic mechanisms that control the availability of micronutrient metals within the cell. Cross-talks between different metal homeostasis pathways within the same bacterial organism have been reported widely. In addition, there have been previous suggestions that some metal uptake transporters can promote adventitious upta...
Article
Full-text available
N‐carbamoyl‐β‐alanine amidohydrolase (CβAA) constitutes one of the most important groups of industrially relevant enzymes used in the production of optically pure amino acids and derivatives. In this study, a CβAA‐encoding gene from Rhizobium radiobacter strain MDC 8606 was cloned and overexpressed in Escherichia coli. The purified recombinant enzy...
Article
Full-text available
The control of nutrient availability is an essential ecological function of the host organism in host-microbe systems. Although often overshadowed by macronutrients such as carbohydrates, micronutrient metals are known as key drivers of host-microbe interactions. The ways in which host organisms control nutrient metal availability are dictated by p...
Article
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Antimicrobial peptides (AMPs) are essential components of innate immunity across all species. AMPs have become the focus of attention in recent years, as scientists are addressing antibiotic resistance, a public health crisis that has reached epidemic proportions. This family of peptides represents a promising alternative to current antibiotics due...
Article
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Histatin-5 (Hst5) is a member of the histatin superfamily of cationic, His-rich, Zn(II)-binding peptides in human saliva. Hst5 displays antimicrobial activity against fungal and bacterial pathogens, often in a Zn(II)-dependent manner. In contrast, here we showed that under in vitro conditions that are characteristic of human saliva, Hst5 does not k...
Preprint
Antimicrobial peptides (AMPs) are essential components of innate immunity across all species. AMPs have become the focus of attention in recent years as scientists are addressing antibiotic resistance, a public health crisis that has reached epidemic proportions. This family of peptides are a promising alternative to current antibiotics due to thei...
Article
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Copper Pyrithione, [Cu(PyS) 2 ] has shown excellent biological activity against cancer cells and bacterial cells, however, it has extremely low aqueous solubility, limiting its applicability. Herein, we report a series of...
Preprint
Full-text available
All bacteria possess homeostastic mechanisms that control the availability of micronutrient metals within the cell. Regulatory cross-talks between different metal homeostasis pathways within the same bacterial organism have been reported widely. In addition, there have been previous suggestions that some metal uptake transporters can promote advent...
Article
Full-text available
Metals are bacterial nutrients. Upon infection by microorganisms, the animal host innate immune system typically reduces the availability of metals. In response, bacterial pathogens can activate pathways for metal uptake to avoid metal starvation. This competition for metals at the host-pathogen interface is termed “nutritional immunity”. We are in...
Article
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Copper (Cu) is an essential micronutrient for cells, but in excess it is cytotoxic. How Cu is cytotoxic is the subject of recent work by L. Zuily, N. Lahrach, R. Fassler, O. Genest, et al. (mBio 13:e03251-21, 2022, https://doi.org/10.1128/mbio.03251-21). Using Escherichia coli as the model cell, the work shows that anoxic cells accumulate larger am...
Article
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The nasopharynx and the skin are the major oxygen-rich anatomical sites for colonization by the human pathogen Streptococcus pyogenes (group A Streptococcus [GAS]). To establish infection, GAS must survive oxidative stress generated during aerobic metabolism and the release of reactive oxygen species (ROS) by host innate immune cells. Glutathione i...
Article
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The introduction of disulfide bonds into periplasmic proteins is a critical process in many Gram-negative bacteria. The formation and regulation of protein disulfide bonds have been linked to the production of virulence factors. Understanding the different pathways involved in this process is important in the development of strategies to disarm pat...
Preprint
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Antimicrobial peptides (AMPs) are key components of diverse host innate immune systems. The family of human salivary AMPs known as histatins bind Zn and Cu. Fluctuations in Zn and Cu availability play significant roles in the host innate immune response (so-called “nutritional immunity”). Thus, we hypothesised that histatins contribute to nutrition...
Article
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The control of intracellular metal availability is fundamental to bacterial physiology. In the case of copper (Cu), it has been established that rising intracellular Cu levels eventually fill the metal-sensing site of the endogenous Cu-sensing transcriptional regulator, which in turn induces transcription of a copper export pump. This response caps...
Article
Metals are bacterial nutrients. Upon infection by microorganisms, the animal host innate immune system typically reduces the availability of metals. In response, bacterial pathogens can activate pathways for metal uptaketo avoid metal starvation. This competition for metals at the host-pathogen interface is termed “nutritional immunity”. We are int...
Preprint
Full-text available
Copper (Cu) is an essential metal for bacterial physiology but in excess it is bacteriotoxic. To limit Cu levels in the cytoplasm, most bacteria possess a transcriptionally-responsive system for Cu export. In the Gram-positive human pathogen Streptococcus pyogenes (Group A Streptococcus , GAS), this system is encoded by the copYAZ operon. In this s...
Article
Bacterial pathogens encounter a variety of adverse physiological conditions during infection, including metal starvation, metal overload and oxidative stress. Here, we demonstrate that group A Streptococcus (GAS) utilises Mn(II) import via MtsABC during conditions of hydrogen peroxide stress to optimally metallate the superoxide dismutase, SodA, wi...
Article
In bacteria, copper (Cu) is often recognised for its potential toxicity and its antibacterial activity is now considered a key component of the mammalian innate immune system. Cu ions bound in weak sites can catalyse harmful redox reactions while Cu ions in strong but adventitious sites can disrupt protein or enzyme function. For these reasons, the...
Article
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Carbapenem-resistant Enterobacteriaceae are an urgent threat to global human health. These organisms produce β-lactamases with carbapenemase activity, such as the metallo-β-lactamase NDM-1, which is notable due to its association with mobile genetic elements and the lack of a clinically useful inhibitor. Here we examined the ability of copper to in...
Article
Lipophilic copper (Cu)-containing complexes have shown promising antibacterial activity against a range of bacterial pathogens. To examine the susceptibility of the intracellular human pathogen Chlamydia trachomatis to copper complexes containing bis(thiosemicarbazone) ligands [Cu(btsc)], we tested the in vitro effect of CuII-diacetyl- and CuII-gly...
Article
Significance Copper (Cu) is an essential trace metal nutrient in health and is increasingly recognized for its role in the control of infection. The pathogen Escherichia coli encounters host niches with mild to high acidity and elevated copper levels. Our study shows that this bacterium can alter its metabolism and harness the amino acid glutamine...
Article
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Streptococcus pyogenes (group A Streptococcus; GAS) is an obligate human pathogen responsible for a broad spectrum of human disease. GAS has a requirement for metal homeostasis within the human host and as such, tightly modulates metal uptake and efflux during infection. Metal acquisition systems are required to combat metal sequestration by the ho...
Chapter
Trace metals such as Fe, Mn, Zn and Cu are essential for various biological functions including proper innate immune function. The host immune system has complicated and coordinated mechanisms in place to either starve and/or overload invading pathogens with various metals to combat the infection. Here, we discuss the roles of Fe, Mn and Zn in term...
Article
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Pathogenic bacteria such as Haemophilus influenzae, a major cause of lower respiratory tract diseases, must cope with a range of electrophiles generated in the host or by endogenous metabolism. Formaldehyde is one such compound that can irreversibly damage proteins and DNA through alkylation and cross-linking and interfere with redox homeostasis. I...
Article
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Formaldehyde is the simplest of all aldehydes and is highly cytotoxic. Its use and associated dangers from environmental exposure have been well documented. Detoxification systems for formaldehyde are found throughout the biological world and they are especially important in methylotrophic bacteria, which generate this compound as part of their met...
Article
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There is increasing interest in the use of lipophilic copper (Cu)-containing complexes to combat bacterial infections. In this work, we showed that Cu complexes with bis(thiosemicarbazone) ligands [Cu(btsc)] exert antibacterial activity against a range of medically significant pathogens. Previous work using Neisseria gonorrhoeae showed that Cu(btsc...
Article
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Zinc (Zn) and copper (Cu) are essential for optimal innate immune function and nutritional deficiency in either metal leads to increased susceptibility to bacterial infection. Recently, the decreased survival of bacterial pathogens with impaired Cu and/or Zn detoxification systems in phagocytes and animal models of infection has been reported. Cons...
Article
Under conditions of low oxygen availability, Neisseria meningitidis and Neisseria gonorrhoeae are able to respire via a partial denitrification pathway in which nitrite is converted to nitrous oxide. In this process, nitrite reductase (AniA), a copper (Cu)-containing protein converts nitrite to NO, and this product is converted to nitrous oxide by...
Article
Several copper(II) complexes of bis(thiosemicarbazones) [(Cu(btsc)s] show promise as therapeutics for the treatment of certain neurological diseases, cancers and bacterial infections. These complexes are thought to act primarily as “copper boosting” agents, whereby the CuII centre is reduced by cytosolic reductants and CuI is released as “free” or...
Article
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Lactate is an abundant metabolite, produced by host tissues and commensal organisms, and it represents an important potential carbon source for bacterial pathogens. In the case of Neisseria spp., the importance of the lactate permease in colonization of the host has been demonstrated, but there have been few studies of lactate metabolism in pathoge...
Article
The copper(ii) complexes of bis-thiosemicarbazones (Cu(btsc)) such as Cu(atsm) and Cu(gtsm) are neutral, lipophilic compounds that show promise as therapeutics for the treatment of certain neurological diseases and cancers. Although the effects of these compounds have been described at the cellular level, there is almost no information about their...
Article
Copper (Cu) is a potent antimicrobial agent. Its use as a disinfectant goes back to antiquity, but this metal ion has recently emerged to have a physiological role in the host innate immune response. Recent studies have identified proteins containing [4Fe-4S] clusters as key targets for inhibition by Cu. However, the way in these effects at the mol...
Article
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NtrYX is a sensor-histidine kinase/response regulator two-component system that has had limited characterization in a small number of Alphaproteobacteria. Phylogenetic analysis of the response regulator NtrX showed that this two-component system is extensively distributed across the bacterial domain, and it is present in a variety of Betaproteobact...
Data
NtrYX is a sensor-histidine kinase/response regulator two-component system that has had limited characterization in a small number of Alphaproteobacteria. Phylogenetic analysis of the response regulator NtrX showed that this two-component system is extensively distributed across the bacterial domain, and it is present in a variety of Betaproteobact...
Article
Full-text available
Aim: The glutathione-dependent AdhC-EstD formaldehyde detoxification system is found in eukaryotes and prokaryotes. It is established that it confers protection against formaldehyde that is produced from environmental sources or methanol metabolism. Thus, its presence in the human host-adapted bacterial pathogen Neisseria meningitidis is intriguin...
Article
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NGO0579 is annotated copA in the Neisseria gonorrhoeae chromosome, suggesting that it encodes a cation-transporting ATPase specific for copper ions. Compared to wild-type cells, a copA mutant was more sensitive to killing by copper ions but not to other transition metals. The mutant also accumulated a greater amount of copper, consistent with the p...
Article
Recognition of the diversity of transcriptional regulators of the MerR family has increased considerably over the last decade and it has been established that not all MerR-like regulators are involved in metal ion recognition. A new type of MerR-like regulator was identified in Neisseria gonorrhoeae that is distinct from metal-binding MerR proteins...
Article
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We have identified a novel regulator from the MerR family of transcription factors in the bacterial pathogen Haemophilus influenzae (HI1623; nickel-associated merR-like Regulator--NimR). NimR regulates the expression of a Ni(2+) uptake transporter (NikKLMQO). The promoters for nimR and the nik operon are divergent and overlapping and NimR binds at...
Article
CueO from Escherichia coli is a multicopper oxidase (MCO) involved in copper tolerance under aerobic conditions. It features four copper atoms that act as electron transfer (T1) and dioxygen reduction (T2, T3; trinuclear) sites. In addition, it displays a methionine-rich insert which includes a helix that blocks physical access to the T1 site and w...
Article
Continuous-wave and pulsed electron paramagnetic resonance have been applied to the study of the CuII site of the copper-resistance protein PcoC from Escherichia coli and certain variant forms. Electron spin echo envelope modulation (ESEEM) experiments confirm the presence of two histidine ligands, His1 and His92, at the CuII site of wild-type PcoC...
Article
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Copper export: PcoA and PcoC are soluble proteins expressed to the periplasm as part of the copper-resistance response of E. coli. PcoC binds both CuI and CuII to form air-stable CuICuII-PcoC. The blue multicopper oxidase PcoA has been shown to catalyze oxidation of CuI bound in CuICuII-PcoC to less toxic CuII, which is released into solution. Thes...
Article
The copper-resistance proteins PcoC from Escherichia coli and CopC from Pseudomonas syringae exhibit 67% sequence identity, but the chemistry reported for PcoC (Peariso, K.; Huffman, D. L.; Penner-Hahn, J. E.; O'Halloran, T. V. J. Am. Chem. Soc. 2003, 125, 342-343) was distinctly different from that reported for CopC (Zhang, L.; Koay, M.; Maher, M....
Chapter
Copper is an essential trace nutrient but when used in slight excess it is highly cytotoxic. This toxicity has been exploited for centuries in medicine and agriculture, and today, the use of copper as an antimicrobial agent is still widespread. Intriguingly, this transition metal ion has recently emerged in a physiological role in the host innate i...

Citations

... 10,16 Among the diverse array of nanomaterials available, organic polymerized nanomaterials offer the advantage of pH-responsive antimicrobial properties and the ability to mimic the actions of antimicrobial peptides to combat bacteria. 17,18 Inorganic metals, 7,19 such as gold 20,21 (Au), silver 22,23 (Ag), and copper 24,25 (Cu), as well as transition metal dichalcogenides 26 (TMDs), metal oxides, 27,28 carbon-based nanomaterials, 29 polymers, and their nanocomposites, have all been prominently utilized in the antibacterial research field. 30 These materials operate through distinct antibacterial mechanisms compared with conventional antibiotics and carry a reduced risk of fostering bacterial resistance. ...
... It is commonly reported that peptide-zinc chelate can improve the bioavailability of intestinal zinc in the human body (Wang et al. 2014). Similarly, previous studies have suggested that peptide-zinc chelates have strong anti-proliferative ability for pathogenic bacteria and simultaneously low toxicity for human body (Donaghy et al. 2023). Despite many researches on the structure and intestinal absorption of peptide-zinc chelates, few studies were devoted to their antimicrobial activity and mechanism. ...
... Taken together, Hst5 is transported to the cytoplasm by binding to RagAB and regulates the expression of genes or proteins related to bacterial biofilm formation and metabolism, and RpoD and FeoB may play important roles in the process of Hst5 inhibiting biofilm formation. In contrast to the role of Hst5 on P. gingivalis, Stewart et al. recently demonstrated that Hst5 failed to kill Streptococci in phosphate buffer or artificial saliva buffer, even in the presence of Zn(II) (Stewart et al. 2023). Differences from our results may be attributed to the bacterial species or experimental conditions because the antimicrobial activity of Hst5 can be influenced by ionic strength and pH. ...
... Aurreko atalean aipaturiko azida eta alkinoen arteko 1,3-zikloadizio dipolar klik erreakzioak baldintza horiek guztiak betetzen ditu, bat izan ezik. Izan ere, katalizatzaile moduan erabiltzen diren kobrearen gatzek zitotoxizitatea erakusten dute eta eragina dute zelulen metabolismoan [47]. Hona hemen 2022. ...
... Therefore, the captured compounds are considered to be potential auxotrophies of S. mutans. In addition, S. mutans is also auxotrophic for glutathione, and the glutathione acquisition from the host is crucial to the S. mutans antioxidant defense system, which facilitates the escape from the host innate immune response (45). ...
... However, the ScsClike proteins show significant heterogeneity in their oligomerization state. Proteus and Caulobacter ScsC form homotrimers connected by the long N-terminal α-helix, while the Salmonella homolog lacking this region is a monomer (116,118) (Fig. 6). These distinct structures seem to be associated with different roles. ...
... Obvious candidates include components of the polydisperse layer of mucus that coats host epithelial tissues, on which symbionts typically reside. For example, mammalian gut mucins [40] and human salivary histatins bind Cu(II) [41]. Do they buffer Cu availability to the mammalian gut and human oral microbiota? ...
... This makes the cellular metal buffers, and the metal transporters that maintain the metal availabilities within the buffered pools, pivotal to cellular physiology. Although the chemical identity of the metal buffers remains largely unknown (14,15), cells must carefully control their abundance as well as the flow of metals into and out of the buffer to maintain the buffered pools within appropriate limits (13). Metal importers must ensure sufficient flux into the buffered pool, as cofactors are drawn out of it for the metalation of enzymes. ...
... In contrast, a GSH-deficient E. coli strain shows no increase in Cu-sensitivity unless CopA is also deleted [158]. Studies using a S. pyogenes ∆copA strain show that mis-metallation in the presence of Cu is reduced when cells grow under GSH supplementation and that GSH competes with CopY for Cu when Cu concentration is high [213]. Thus, GSH that is present at millimolar concentrations inside the cell likely binds Cu primarily when the maximal capacity of Cu chaperones and exporters to bind Cu is consumed. ...
... This transporter plays a crucial role in uptake of manganese and iron (Jakubovics, 2019). Uptake of manganese is critical for the growth of Group A Streptococcus under oxidative conditions (Turner et al., 2019). Also, iron is important for the growth and survival, but the availability of iron in the host is limited (Ge & Sun, 2014). ...