Pseudomonas aeruginosa zinc homeostasis: Key issues for an opportunistic pathogen

Gonzalez, Manuel R.; Ducret, Véréna; Leoni, S; Perron, Karl

doi:10.1016/j.bbagrm.2018.01.018

Cited by 50 publications

(69 citation statements)

References 117 publications

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“…PhoU and PhoB are two of the most influential regulatory proteins in the stress‐sensing phosphate regulon (Pho regulon) and are expressed by most species of bacteria. PhoU is a phosphate uptake regulatory protein and is a component of the phosphate‐specific transport protein system (pst SCAB) . PhoB is a transcriptional regulator of the PhoB‐PhoR two‐component regulatory system during stressor‐induced, phosphate‐limited conditions .…”

Section: Resultsmentioning

confidence: 99%

“…are flagellar, Gram-negative, strict aerobes, and Zn has been identified as a factor important to Pseudomonas virulence and antibiotic resistance. [63] Pseudomonas aeruginosa in particular is an opportunistic pathogen that secretes toxins and is a major cause of infection-related mortality among individuals with compromised immune systems. Gut colonization by P. aeruginosa can set the stage for the underlying development of invasive infection.…”

Section: Changes In Gene Expression In the Host Is Associated With Gumentioning

confidence: 99%

“…PhoU is a phosphate uptake regulatory protein and is a component of the phosphate-specific transport protein system (pst SCAB). [63] PhoB is a transcriptional regulator of the PhoB-PhoR two-component regulatory system during stressor-induced, phosphate-limited conditions. [64] Interestingly, the expression of PhoU (p < 0.01) and PhoB (p < 0.01) were significantly higher (more than twofold) following excess Zn exposure (Figure 9).…”

Section: Changes In Gene Expression In the Host Is Associated With Gumentioning

confidence: 99%

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Excess Dietary Zinc Intake in Neonatal Mice Causes Oxidative Stress and Alters Intestinal Host–Microbe Interactions

Podany

Rauchut

et al. 2018

Molecular Nutrition Food Res

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Scope Greater than 68% of young infants are exposed to dietary zinc (Zn) levels that are higher than the Tolerable Upper Intake Limit. However, the consequences of excess dietary Zn during early life on intestinal function and host–microbe interactions are unknown. Methods and Results Neonatal mice are gavaged with 100 Zn µg d–1 from postnatal day (PN) 2 through PN10 and indices of intestinal function and host–microbe interactions are compared to unsupplemented mice. Excess dietary Zn causes oxidative stress, increases goblet cell number and mucus production, and are associated with increased intestinal permeability and systemic inflammation. Over 900 genes are differentially expressed; 413 genes display a fold‐change >1.60. The Gene Ontology Biological processes most significantly affected include biological adhesion, the immune system, metabolic processes, and response to stimulus. Key genes most highly and significantly upregulated include ALDH2, MT1, TMEM6, CDK20, and COX62b, while CALU, ST3GAL4, CRTC2, SLC28A2, and COMMA1 are downregulated. These changes are associated with a microbiome enriched in pathogenic taxa including Pseudomonadales and Campylobacter, and greater expression of bacterial stress response genes. Conclusion Excess dietary Zn may have unforeseen influences on epithelial signaling pathways, barrier function, and luminal ecology in the intestine that may have long‐term consequences on intestinal health.

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Section: Resultsmentioning

confidence: 99%

Section: Changes In Gene Expression In the Host Is Associated With Gumentioning

confidence: 99%

Section: Changes In Gene Expression In the Host Is Associated With Gumentioning

confidence: 99%

See 1 more Smart Citation

Excess Dietary Zinc Intake in Neonatal Mice Causes Oxidative Stress and Alters Intestinal Host–Microbe Interactions

Podany

Rauchut

et al. 2018

Molecular Nutrition Food Res

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“…The pseudopaline system is primarily involved in zinc uptake in zinc poor environments and zinc transport into the cell is achieved via the action of a four-gene operon ( cntOLMI , also termed zrmABCD ) (38, 39). This operon includes the genes for a TonB-dependent outer membrane pseudopaline receptor (CntO), two biosynthetic enzymes (CntL and CntM) responsible for synthesizing pseudopaline and an inner membrane transporter (CntI) involved in pseudopaline secretion (36, 38, 39). Both the ZnuABC system and the pseudopaline operon are negatively regulated by zinc level through the Fur-like zinc uptake regulator Zur (35, 37, 39), which can sense and respond to femtomolar changes of cytosolic zinc concentrations (41).…”

Section: Introductionmentioning

confidence: 99%

“…Both the ZnuABC system and the pseudopaline operon are negatively regulated by zinc level through the Fur-like zinc uptake regulator Zur (35, 37, 39), which can sense and respond to femtomolar changes of cytosolic zinc concentrations (41). When zinc is bound, Zur represses transcription of the zinc uptake systems and loss of Zur results in higher cytoplasmic zinc in P. aeruginosa (36, 37).…”

Section: Introductionmentioning

confidence: 99%

Availability of Zinc Impacts Interactions BetweenStreptococcus sanguinisandPseudomonas aeruginosain Co-culture

Gifford

Hampton

et al. 2019

Preprint

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23Airway infections associated with cystic fibrosis (CF) are polymicrobial. We reported 24 previously that clinical isolates of P. aeruginosa promote the growth of a variety of 25 streptococcal species. To explore the mechanistic basis of this interaction, we performed a 26 genetic screen to identify mutants of Streptococcus sanginuis SK36 whose growth was no 27 longer enhanced by P. aeruginosa PAO1. Mutations in zinc uptake systems of S. sanginuis 28 SK36 reduced growth of these strains by 1-3 log compared to wild-type S. sanginuis SK36 29 when grown in coculture with P. aeruginosa PA01, while exogenous zinc (0.1-10 μm) rescued 30 the coculture defect of zinc uptake mutants of S. sanginuis SK36. Zinc uptake mutants of S. 31 sanginuis SK36 had no obvious growth defect in monoculture. Consistent with a competition 32 for zinc driving coculture dynamics, S. sanginuis SK36 grown in coculture with P. aeruginosa 33 showed increased expression of zinc uptake genes compared to S. sanginuis grown alone. 34 Strains of P. aeruginosa PAO1 defective in zinc transport also supported more robust growth 35 by S. sanginuis compared to coculture with wild-type P. aeruginosa PAO1. An analysis of 118 36 CF sputum samples revealed that total zinc levels varied from ~5-145 μM. At relatively low 37 zinc levels, Pseudomonas and Streptococcus were found in approximately equal abundance; 38 at higher zinc levels, we observed an increasing relative abundance of Pseudomonas and 39 decline of Streptococcus, perhaps as a result of increasing zinc toxicity. Together, our data 40 indicate that the relative abundance of these microbes in the CF airway may be impacted by 41 zinc levels. 42 IMPORTANCE. Polymicrobial infections in CF likely impact patient health, but the 43 mechanism(s) underlying such interactions are poorly understood. Here we show that 44 interactions between Pseudomonas and Streptococcus are modulated by zinc availability 45 using an in vitro model system, and clinical data are consistent with this model. Together with 46 previous studies, our work supports a role for metal homeostasis as a key factor driving 47 49Cystic fibrosis (CF) is a monogenic autosomal recessive disorder caused by mutations in the 50 cystic fibrosis transmembrane conductance regulator (CFTR) gene (1). It is estimated that 51 ~70,000 individuals in the world are affected by CF and the most common mutation, caused 52 by a deletion of phenylalanine at the 508th amino acid within the CFTR protein (ΔF508), is 53 found in approximately 70% of this population (2, 3). CFTR dysfunction affects several body 54 systems, and progressive lung disease due to chronic and recurrent microbial infections is 55 the leading cause of morbidity and mortality in individuals with CF (4, 5). It has been shown 56 that CF airway infections are polymicrobial (6, 7), and the composition and interspecies 57 interactions within the polymicrobial communities can have profound and diverse 58 consequences, including on bacterial growth (8-10), as well as disease progression and 59 thera...

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Transition metal cation inhibition of Mycobacterium tuberculosis esterase RV0045C

et al. 2021

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Mycobacterium tuberculosis virulence is highly metal-dependent with metal availability modulating the shift from the dormant to active states of M. tuberculosis infection. Rv0045c from M. tuberculosis is a proposed metabolic serine hydrolase whose folded stability is dependent on divalent metal concentration. Herein, we measured the divalent metal inhibition profile of the enzymatic activity of Rv0045c and found specific divalent transition metal cations) strongly inhibited its enzymatic activity. The metal cations bind allosterically, largely affecting values for k cat rather than K M . Removal of the artificial N-terminal 6xHis-tag did not change the metaldependent inhibition, indicating that the allosteric inhibition site is native to Rv0045c. To isolate the site of this allosteric regulation in Rv0045c, the structures of Rv0045c were determined at 1.8 Å and 2.0 Å resolution in the presence and absence of Zn 2+ with each structure containing a previously unresolved dynamic loop spanning the binding pocket. Through the combination of structural analysis with and without zinc and targeted mutagenesis, this metaldependent inhibition was traced to multiple chelating residues (H202A/ E204A) on a flexible loop, suggesting dynamic allosteric regulation of Rv0045c by divalent metals. Although serine hydrolases like Rv0045c are a large and diverse enzyme superfamily, this is the first structural confirmation of allosteric regulation of their enzymatic activity by divalent metals.

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Pseudomonas aeruginosa zinc homeostasis: Key issues for an opportunistic pathogen

Cited by 50 publications

References 117 publications

Excess Dietary Zinc Intake in Neonatal Mice Causes Oxidative Stress and Alters Intestinal Host–Microbe Interactions

Excess Dietary Zinc Intake in Neonatal Mice Causes Oxidative Stress and Alters Intestinal Host–Microbe Interactions

Availability of Zinc Impacts Interactions BetweenStreptococcus sanguinisandPseudomonas aeruginosain Co-culture

Transition metal cation inhibition of Mycobacterium tuberculosis esterase RV0045C

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