Strategies for Zinc Uptake in Pseudomonas aeruginosa at the Host–Pathogen Interface

As a structural, catalytic, and signaling component, zinc is necessary for the growth and development of plants, animals, and microorganisms. Zinc is also essential for the growth of pathogenic microorganisms and is involved in their metabolism as well as the regulation of various virulence factors. Additionally, zinc is necessary for infection and colonization of pathogenic microorganisms in the host. Upon infection in healthy organisms, the host sequesters zinc both intracellularly and extracellularly to enhance the immune response and prevent the proliferation and infection of the pathogen. Intracellularly, the host manipulates zinc levels through Zrt/Irt-like protein (ZIP)/ZnT family proteins and various zinc storage proteins. Extracellularly, members of the S100 protein family, such as calgranulin C, sequester zinc to inhibit microbial growth. In the face of these nutritional limitations, bacteria rely on an efficient zinc transport system to maintain zinc supplementation for proliferation and disruption of the host defense system to establish infection. Here, we summarize the strategies for zinc uptake in conditional pathogenic Pseudomonas aeruginosa, including known zinc uptake systems (ZnuABC, HmtA, and ZrmABCD) and the zinc uptake regulator (Zur). In addition, other potential zinc uptake pathways were analyzed. This review systematically summarizes the process of zinc uptake by P. aeruginosa to provide guidance for the development of new drug targets.

Download Full-text

Availability of Zinc Impacts Interactions between Streptococcus sanguinis and Pseudomonas aeruginosa in Coculture

Journal of Bacteriology ◽

10.1128/jb.00618-19 ◽

2019 ◽

Vol 202 (2) ◽

Author(s):

Kewei Li ◽

Alex H. Gifford ◽

Thomas H. Hampton ◽

George A. O’Toole

Keyword(s):

Pseudomonas Aeruginosa ◽

Zinc Uptake ◽

Microbial Interactions ◽

Growth Defect ◽

Zinc Toxicity ◽

Wild Type ◽

Content Type ◽

Airway Infections ◽

Zinc Levels

ABSTRACT Airway infections associated with cystic fibrosis (CF) are polymicrobial. We reported previously that clinical isolates of Pseudomonas aeruginosa promote the growth of a variety of streptococcal species. To explore the mechanistic basis of this interaction, we performed a genetic screen to identify mutants of Streptococcus sanginuis SK36 whose growth was no longer enhanced by P. aeruginosa PAO1. Mutations in the zinc uptake systems of S. sanguinis SK36 reduced growth of these strains by 1 to 3 logs compared to that of wild-type S. sanguinis SK36 when grown in coculture with P. aeruginosa PAO1, and exogenous zinc (0.1 to 10 μM) rescued the coculture defect of zinc uptake mutants of S. sanguinis SK36. Zinc uptake mutants of S. sanguinis SK36 had no obvious growth defect in monoculture. Consistent with competition for zinc driving coculture dynamics, S. sanguinis SK36 grown in coculture with P. aeruginosa showed increased expression of zinc uptake genes compared to that of S. sanguinis grown alone. Strains of P. aeruginosa PAO1 defective in zinc transport also supported ∼2-fold more growth by S. sanguinis compared to that in coculture with wild-type P. aeruginosa PAO1. An analysis of 118 CF sputum samples revealed that total zinc levels varied from ∼5 to 145 μM. At relatively low zinc levels, Pseudomonas and Streptococcus spp. were found in approximately equal abundance; at higher zinc levels, we observed a decline in relative abundance of Streptococcus spp., perhaps as a result of increasing zinc toxicity. Together, our data indicate that the relative abundances of these microbes in the CF airway may be impacted by zinc levels. IMPORTANCE Polymicrobial infections in CF cases likely impact patient health, but the mechanism(s) underlying such interactions is poorly understood. Here, we show using an in vitro model system that interactions between Pseudomonas and Streptococcus are modulated by zinc availability, and clinical data are consistent with this model. Together with previous studies, our work supports a role for metal homeostasis as a key factor driving microbial interactions.

Download Full-text

The Transcriptional Regulator Np20 Is the Zinc Uptake Regulator in Pseudomonas aeruginosa

PLoS ONE ◽

10.1371/journal.pone.0075389 ◽

2013 ◽

Vol 8 (9) ◽

pp. e75389 ◽

Cited By ~ 28

Author(s):

Matthew L. Ellison ◽

John Matthew Farrow ◽

Whitney Parrish ◽

Allison S. Danell ◽

Everett C. Pesci

Keyword(s):

Pseudomonas Aeruginosa ◽

Transcriptional Regulator ◽

Zinc Uptake ◽

Zinc Uptake Regulator

Download Full-text

Correction: The Transcriptional Regulator Np20 Is the Zinc Uptake Regulator in Pseudomonas aeruginosa

PLoS ONE ◽

10.1371/annotation/40be2093-f3d0-41ca-a8d7-02fecd051942 ◽

2013 ◽

Vol 8 (10) ◽

Cited By ~ 1

Author(s):

Matthew L. Ellison ◽

John M. Farrow ◽

Whitney Parrish ◽

Allison S. Danell ◽

Everett C. Pesci

Keyword(s):

Pseudomonas Aeruginosa ◽

Transcriptional Regulator ◽

Zinc Uptake ◽

Zinc Uptake Regulator

Download Full-text

Microflora in External Auditory Canals of Recreational Scuba-Divers and Swimmers Related to the Tropical Waterflora of a Coral Island

Water Science & Technology ◽

10.2166/wst.1993.0344 ◽

1993 ◽

Vol 27 (3-4) ◽

pp. 187-193

Author(s):

T. Haider ◽

R. Sommer ◽

G. Stanek

Keyword(s):

Pseudomonas Aeruginosa ◽

Water Supply ◽

External Auditory Canal ◽

Pathogenic Microorganisms ◽

Lagoon Water ◽

Scuba Divers ◽

Tropical Coral ◽

Coral Island ◽

Recreational Scuba ◽

The Tropics

Recent studies described the acute diffuse external otitis frequently observed in recreational scuba-divers and swimmers in the tropics. In this study the microflora of the external auditory canal of 90 persons was determined. Additionally, a group of 17 persons was examined before, during and at the end of a two weeks vacation on a tropical coral island as well as three months after. Further, samples from sea, lagoon water and the water supplies used for the showers were microbiologically examined. 14 different and fecultatively pathogenic microorganisms were isolated from the external auditory canals. We found a temporary colonization with those microorganisms during the two weeks. Above all Pseudomonas aeruginosa was predominant during and at the end of the vacation especially in children. Before the vacation and three months after P. aeruginosa could not be found. The samples of sea and lagoon waters did not seem to be noticeably polluted, whereas the samples of the water supply were extremely contaminated with Pseudomonas aeruginosa. It was concluded that besides indirect factors such as tropical climate and intensive exposition to water, the insufficient treatment of the water from the supply could also be a reason for the temporary microbiological colonization of the external auditory canal.

Download Full-text

Zinc Uptake Regulator (zur) Gene Involved in Zinc Homeostasis and Virulence of Xanthomonas oryzae pv. oryzae in Rice

Current Microbiology ◽

10.1007/s00284-006-0485-8 ◽

2007 ◽

Vol 54 (4) ◽

pp. 307-314 ◽

Cited By ~ 29

Author(s):

Wanfeng Yang ◽

Yan Liu ◽

Lei Chen ◽

Tongchun Gao ◽

Baishi Hu ◽

...

Keyword(s):

Zinc Uptake ◽

Xanthomonas Oryzae ◽

Zinc Homeostasis ◽

Zinc Uptake Regulator

Download Full-text

Pseudomonas aeruginosa and Staphylococcus aureus virulence factors as biomarkers of infection

Biological Chemistry ◽

10.1515/hsz-2021-0243 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Artur J. Sabat ◽

Daniele Pantano ◽

Viktoria Akkerboom ◽

Erik Bathoorn ◽

Alexander W. Friedrich

Keyword(s):

Staphylococcus Aureus ◽

Pseudomonas Aeruginosa ◽

Bacterial Infections ◽

Clinical Status ◽

Clinical Samples ◽

Pathogenic Microorganisms ◽

Bacterial Identification ◽

Accurate Identification ◽

Culture Independent ◽

And Staphylococcus Aureus

Abstract The gold standard for the diagnosis of bacterial infections in clinical samples is based on culture tests that are time-consuming and labor-intense. For these reasons, an extraordinary effort has been made to identify biomarkers as the tools for sensitive, rapid and accurate identification of pathogenic microorganisms. Moreover, biomarkers have been tested to distinguish colonization from infection, monitor disease progression, determine the clinical status of patients or predict clinical outcomes. This mini-review describes Pseudomonas aeruginosa and Staphylococcus aureus biomarkers, which contribute to pathogenesis and have been used in culture-independent bacterial identification directly from patient samples.

Download Full-text

In vitro synergy of ceftolozane/tazobactam in combination with fosfomycin or aztreonam against MDR Pseudomonas aeruginosa

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkaa095 ◽

2020 ◽

Vol 75 (7) ◽

pp. 1874-1878 ◽

Cited By ~ 3

Author(s):

Gabriel T Cuba ◽

Gerlan Rocha-Santos ◽

Rodrigo Cayô ◽

Ana Paula Streling ◽

Carolina S Nodari ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Resistance Mechanisms ◽

Density Reduction ◽

Carbapenem Resistant ◽

Gradient Diffusion ◽

Fold Reduction ◽

The Face ◽

Antimicrobial Synergy ◽

Time Kill

Abstract Objectives Carbapenem-resistant Pseudomonas aeruginosa (CR-PSA) imposes great limitations on empirical therapeutic choices, which are further complicated by metallo-β-lactamase production. This study evaluated in vitro antimicrobial synergy of ceftolozane/tazobactam in combination with aztreonam and fosfomycin against MDR PSA. Methods MICs were determined by broth microdilution and gradient strips. The effect of ceftolozane/tazobactam+aztreonam and ceftolozane/tazobactam+fosfomycin combinations were tested against 27 MDR PSA isolates carrying blaSPM-1 (n = 13), blaIMP (n = 4), blaVIM (n = 3), blaGES-1 (n = 2) and blaCTX-M-like (n = 2), and 3 isolates with no acquired β-lactamase production detected by gradient diffusion strip crossing (GDSC). Six genetically unrelated SPM-1-producing isolates were also evaluated by time–kill analysis (TKA). Results All CR-PSA isolates harbouring blaSPM-1, blaGES-1 and blaIMP-1 were categorized as resistant to ceftolozane/tazobactam, meropenem and fosfomycin, with 70% being susceptible to aztreonam. Synergism for ceftolozane/tazobactam+fosfomycin and ceftolozane/tazobactam+aztreonam combinations was observed for 88.9% (24/27) and 18.5% (5/27) of the isolates by GDSC, respectively. A 3- to 9-fold reduction in ceftolozane/tazobactam MICs was observed, depending on the combination. Ceftolozane/tazobactam+fosfomycin was synergistic by TKA against one of six SPM-1-producing isolates, with additional non-synergistic bacterial density reduction for another isolate. Aztreonam peak concentrations alone demonstrated a ≥3 log10 cfu/mL reduction against all six isolates, but all strains were within the susceptible range for the drug. No antagonism was observed. Conclusions In the context of increasing CR-PSA and the genetic diversity of resistance mechanisms, new combinations and stewardship strategies may need to be explored in the face of increasingly difficult to treat pathogens.

Download Full-text

Saccharomyces cerevisiae Vacuole in Zinc Storage and Intracellular Zinc Distribution

Eukaryotic Cell ◽

10.1128/ec.00077-07 ◽

2007 ◽

Vol 6 (7) ◽

pp. 1166-1177 ◽

Cited By ~ 65

Author(s):

Claudia Simm ◽

Brett Lahner ◽

David Salt ◽

Ann LeFurgey ◽

Peter Ingram ◽

...

Keyword(s):

Saccharomyces Cerevisiae ◽

Growth Conditions ◽

Zinc Uptake ◽

Zinc Status ◽

Absolute Level ◽

Intracellular Zinc ◽

Fractionation Method ◽

State Growth ◽

Zinc Levels ◽

Zinc Storage

ABSTRACT Previous studies of the yeast Saccharomyces cerevisiae indicated that the vacuole is a major site of zinc storage in the cell. However, these studies did not address the absolute level of zinc that was stored in the vacuole nor did they examine the abundances of stored zinc in other compartments of the cell. In this report, we describe an analysis of the cellular distribution of zinc by use of both an organellar fractionation method and an electron probe X-ray microanalysis. With these methods, we determined that zinc levels in the vacuole vary with zinc status and can rise to almost 100 mM zinc (i.e., 7 × 108 atoms of vacuolar zinc per cell). Moreover, this zinc can be mobilized effectively to supply the needs of as many as eight generations of progeny cells under zinc starvation conditions. While the Zrc1 and Cot1 zinc transporters are essential for zinc uptake into the vacuole under steady-state growth conditions, additional transporters help mediate zinc uptake into the vacuole during “zinc shock,” when zinc-limited cells are resupplied with zinc. In addition, we found that other compartments of the cell do not provide significant stores of zinc. In particular, zinc accumulation in mitochondria is low and is homeostatically regulated independently of vacuolar zinc storage. Finally, we observed a strong correlation between zinc status and the levels of magnesium and phosphorus accumulated in cells. Our results implicate zinc as a major determinant of the ability of the cell to store these other important nutrients.

Download Full-text

Functional Definition and Global Regulation of Zur, a Zinc Uptake Regulator in a Streptococcus suis Serotype 2 Strain Causing Streptococcal Toxic Shock Syndrome

Journal of Bacteriology ◽

10.1128/jb.01532-07 ◽

2008 ◽

Vol 190 (22) ◽

pp. 7567-7578 ◽

Cited By ~ 41

Author(s):

Youjun Feng ◽

Ming Li ◽

Huimin Zhang ◽

Beiwen Zheng ◽

Huiming Han ◽

...

Keyword(s):

Toxic Shock Syndrome ◽

Streptococcus Suis ◽

Gene Replacement ◽

Zinc Uptake ◽

Zinc Homeostasis ◽

Differentially Expressed ◽

Streptococcal Toxic Shock Syndrome ◽

Toxic Shock ◽

Physiological Tests ◽

Zinc Uptake Regulator

ABSTRACT Zinc is an essential trace element for all living organisms and plays pivotal roles in various cellular processes. However, an excess of zinc is extremely deleterious to cells. Bacteria have evolved complex machineries (such as efflux/influx systems) to control the concentration at levels appropriate for the maintenance of zinc homeostasis in cells and adaptation to the environment. The Zur (zinc uptake regulator) protein is one of these functional members involved in the precise control of zinc homeostasis. Here we identified a zur homologue designated 310 from Streptococcus suis serotype 2, strain 05ZYH33, a highly invasive isolate causing streptococcal toxic shock syndrome. Biochemical analysis revealed that the protein product of gene 310 exists as a dimer form and carries zinc ions. An isogenic gene replacement mutant of gene 310, the Δ310 mutant, was obtained by homologous recombination. Physiological tests demonstrated that the Δ310 mutant is specifically sensitive to Zn2+, while functional complementation of the Δ310 mutant can restore its duration capability, suggesting that 310 is a functional member of the Zur family. Two-dimensional electrophoresis indicated that nine proteins in the Δ310 mutant are overexpressed in comparison with those in the wild type. DNA microarray analyses suggested that 121 genes in the Δ310 mutant are affected, of which 72 genes are upregulated and 49 are downregulated. The transcriptome of S. suis serotype 2 with high Zn2+ concentrations also showed 117 differentially expressed genes, with 71 upregulated and 46 downregulated. Surprisingly, more than 70% of the genes differentially expressed in the Δ310 mutant were the same as those in S. suis serotype 2 that were differentially expressed in response to high Zn2+ concentration, consistent with the notion that 310 is involved in zinc homeostasis. We thus report for the first time a novel zinc-responsive regulator, Zur, from Streptococcus suis serotype 2.

Download Full-text