11 research outputs found
Evolutionary Conservation of Zinc-Mediated Nutritional Immunity Across Vertebrates and Insects in Host-Pathogen Interactions
No full textSalmonella typhimurium and pseudomonas aeruginosa respond differently to the fe chelator deferiprone and to some novel deferiprone derivatives
No full textThe ability to obtain Fe is critical for pathogens to multiply in their host. For this reason,
there is significant interest in the identification of compounds that might interfere with Fe management in bacteria. Here we have tested the response of two Gram-negative pathogens, Salmonella
enterica serovar Typhimurium (STM) and Pseudomonas aeruginosa (PAO1), to deferiprone (DFP),
a chelating agent already in use for the treatment of thalassemia, and to some DFP derivatives
designed to increase its lipophilicity. Our results indicate that DFP effectively inhibits the growth of
PAO1, but not STM. Similarly, Fe-dependent genes of the two microorganisms respond differently to
this agent. DFP is, however, capable of inhibiting an STM strain unable to synthesize enterochelin,
while its effect on PAO1 is not related to the capability to produce siderophores. Using a fluorescent
derivative of DFP we have shown that this chelator can penetrate very quickly into PAO1, but not
into STM, suggesting that a selective receptor exists in Pseudomonas. Some of the tested derivatives
have shown a greater ability to interfere with Fe homeostasis in STM compared to DFP, whereas
most, although not all, were less active than DFP against PAO1, possibly due to interference of the
added chemical tails with the receptor-mediated recognition process. The results reported in this
work indicate that DFP can have different effects on distinct microorganisms, but that it is possible to
obtain derivatives with a broader antimicrobial actio
G. mellonella is a suitable model for studying P. aeruginosa response to the host nutritional immunity strategies
No full textPseudomonas aeruginosa transcriptional reprogramming during zinc starvation reveals a shift toward anaerobic respiration
No full textLocalized Infections with P. aeruginosa Strains Defective in Zinc Uptake Reveal That Zebrafish Embryos Recapitulate Nutritional Immunity Responses of Higher Eukaryotes
Get PDFThe innate immune responses of mammals to microbial infections include strategies based on manipulating the local concentration of metals such as iron (Fe) and zinc (Zn), commonly described as nutritional immunity. To evaluate whether these strategies are also present in zebrafish embryos, we have conducted a series of heart cavity-localized infection experiments with Pseudomonas aeruginosa strains characterized by a different ability to acquire Zn. We have found that, 48 h after infection, the bacterial strains lacking critical components of the Zn importers ZnuABC and ZrmABCD have a reduced colonization capacity compared to the wild-type strain. This observation, together with the finding of a high level of expression of Zur-regulated genes, suggests the existence of antimicrobial mechanisms based on Zn sequestration. However, we have observed that strains lacking such Zn importers have a selective advantage over the wild-type strain in the early stages of infection. Analysis of the expression of the gene that encodes for a Zn efflux pump has revealed that at short times after infection, P. aeruginosa is exposed to high concentrations of Zn. At the same time, zebrafish respond to the infection by activating the expression of the Zn transporters Slc30a1 and Slc30a4, whose mammalian homologs mediate a redistribution of Zn in phagocytes aimed at intoxicating bacteria with a metal excess. These observations indicate that teleosts share similar nutritional immunity mechanisms with higher vertebrates, and confirm the usefulness of the zebrafish model for studying host–pathogen interactions
Zinc-binding metallophores protect Pseudomonas aeruginosa from calprotectin-mediated metal starvation
No full textThe ability to produce a metallophore that can extract the metal from zinc-binding proteins contributes to the remarkable ability of Pseudomona aeruginosa to proliferate in zinc-poor environments.Pseudomonas aeruginosa is known to exhibit considerable resistance to the antimicrobial activity of the metal-sequestering protein calprotectin (CP). In this study, we demonstrate that although CP induces zinc deficiency in P. aeruginosa, a strain unable to import zinc through the two most important metal acquisition systems, namely ZnuABC and ZrmABCD, maintains significant growth capacity in the presence of high concentrations of CP. Furthermore, we have shown that nicotianamine, a molecule structurally similar to the metallophore pseudopaline, can favor the acquisition of the metal even in the presence of CP. To gain insights into the mechanisms through which metallophores can promote zinc acquisition, we analyzed the effect of nicotianamine on the activity of the metallo-beta-lactamase VIM-1. Our data suggest that metallophores released by bacteria in response to zinc deficiency can extract the protein-bound metal. The ability to interfere with the binding of metals to proteins, as well as favoring the acquisition of zinc, may contribute to increasing the resistance of P. aeruginosa to the antimicrobial action of CP
Investigation of Zur-regulated metal transport systems reveals an unexpected role of pyochelin in zinc homeostasis
Get PDFLimiting the availability of transition metals at infection sites serves as a critical defense mechanism employed by the innate immune system to combat microbial infections. Pseudomonas aeruginosa exhibits a remarkable ability to thrive in zinc-deficient environments, which is facilitated by intricate cellular responses governed by numerous genes regulated by the zinc-responsive transcription factor Zur. Many of these genes have unknown functions, including those within the predicted PA2911-PA2914 and PA4063-PA4066 operons. A bioinformatic analysis revealed that PA2911-PA2914 comprises a TonB-dependent outer membrane receptor and an inner membrane ABC-permease responsible for importing metal-chelating molecules, whereas PA4063-PA4066 contains genes encoding a MacB transporter, likely involved in the export of large molecules. Molecular genetics and biochemical experiments, feeding assays, and intracellular metal content measurements demonstrated that PA2911-PA2914 and PA4063-PA4066 are engaged in the import and export of the pyochelin-cobalt complex, respectively. Notably, cobalt can reduce zinc demand and promote the growth of P. aeruginosa strains unable to import zinc, highlighting pyochelin-mediated cobalt import as a novel bacterial strategy to counteract zinc deficiency. These results unveil an unexpected role for pyochelin in zinc homeostasis and challenge the traditional view of this metallophore exclusively as an iron transporter
Siderophore or metallophore? An inves?ga?on of Zur-regulated metal transport systems reveals an unexpected role of pyochelin in zinc homeostasis
No full textSYNTHESIS AND STRUCTURE-ACTIVITY RELATIONSHIPS OF PSEUDOPALINE AND ITS MOLECULAR SIMPLIFICATION DERIVATIVES AS CANDIDATES FOR ZINCOPHORE-ANTIBIOTICS CONJUGATES DEVELOPMENT
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