International Journal of Molecular Sciences

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Open AccessEditorial

New Insights into the Role of Metals in Host–Pathogen Interactions

by Serena Ammendola and Andrea Battistoni

Int. J. Mol. Sci. 2022, 23(12), 6483; https://doi.org/10.3390/ijms23126483 - 10 Jun 2022

Viewed by 978

Abstract

Almost eighty years have passed since the publication of the studies by Arthur Schade and Leona Caroline, which we can consider as the first investigations that began to disclose the importance of metals in host–pathogen interactions [...] Full article

(This article belongs to the Special Issue Transition Metals in the Host-Pathogen Interaction)

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15 pages, 1892 KiB

Open AccessArticle

A Comparative Study on Nickel Binding to Hpn-like Polypeptides from Two Helicobacter pylori Strains

by Danuta Witkowska, Agnieszka Szebesczyk, Joanna Wątły, Michał Braczkowski and Magdalena Rowińska-Żyrek

Int. J. Mol. Sci. 2021, 22(24), 13210; https://doi.org/10.3390/ijms222413210 - 08 Dec 2021

Cited by 3 | Viewed by 2004

Abstract

Combined potentiometric titration and isothermal titration calorimetry (ITC) methods were used to study the interactions of nickel(II) ions with the N-terminal fragments and histidine-rich fragments of Hpn-like protein from two Helicobacter pylori strains (11637 and 26695). The ITC measurements were performed at various [...] Read more.

Combined potentiometric titration and isothermal titration calorimetry (ITC) methods were used to study the interactions of nickel(II) ions with the N-terminal fragments and histidine-rich fragments of Hpn-like protein from two Helicobacter pylori strains (11637 and 26695). The ITC measurements were performed at various temperatures and buffers in order to extract proton-independent reaction enthalpies of nickel binding to each of the studied protein fragments. We bring up the problem of ITC results of nickel binding to the Hpn-like protein being not always compatible with those from potentiometry and MS regarding the stoichiometry and affinity. The roles of the ATCUN motif and multiple His and Gln residues in Ni(II) binding are discussed. The results provided the possibility to compare the Ni(II) binding properties between N-terminal and histidine-rich part of Hpn-like protein and between N-terminal parts of two Hpn-like strains, which differ mainly in the number of glutamine residues. Full article

(This article belongs to the Special Issue Transition Metals in the Host-Pathogen Interaction)

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15 pages, 2754 KiB

Open AccessArticle

Salmonella Typhimurium and Pseudomonas aeruginosa Respond Differently to the Fe Chelator Deferiprone and to Some Novel Deferiprone Derivatives

by Serena Ammendola, Valerio Secli, Francesca Pacello, Martina Bortolami, Fabiana Pandolfi, Antonella Messore, Roberto Di Santo, Luigi Scipione and Andrea Battistoni

Int. J. Mol. Sci. 2021, 22(19), 10217; https://doi.org/10.3390/ijms221910217 - 23 Sep 2021

Cited by 5 | Viewed by 1728

Abstract

The 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 [...] Read more.

The 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 action. Full article

(This article belongs to the Special Issue Transition Metals in the Host-Pathogen Interaction)

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23 pages, 4014 KiB

Open AccessArticle

The bZIP Transcription Factor HapX Is Post-Translationally Regulated to Control Iron Homeostasis in Aspergillus fumigatus

by Manuel Sánchez López-Berges, Mareike Thea Scheven, Peter Hortschansky, Matthias Misslinger, Clara Baldin, Fabio Gsaller, Ernst R. Werner, Thomas Krüger, Olaf Kniemeyer, Jakob Weber, Axel A. Brakhage and Hubertus Haas

Int. J. Mol. Sci. 2021, 22(14), 7739; https://doi.org/10.3390/ijms22147739 - 20 Jul 2021

Cited by 10 | Viewed by 2351

Abstract

The airborne fungus Aspergillus fumigatus causes opportunistic infections in humans with high mortality rates in immunocompromised patients. Previous work established that the bZIP transcription factor HapX is essential for virulence via adaptation to iron limitation by repressing iron-consuming pathways and activating iron acquisition [...] Read more.

The airborne fungus Aspergillus fumigatus causes opportunistic infections in humans with high mortality rates in immunocompromised patients. Previous work established that the bZIP transcription factor HapX is essential for virulence via adaptation to iron limitation by repressing iron-consuming pathways and activating iron acquisition mechanisms. Moreover, HapX was shown to be essential for transcriptional activation of vacuolar iron storage and iron-dependent pathways in response to iron availability. Here, we demonstrate that HapX has a very short half-life during iron starvation, which is further decreased in response to iron, while siderophore biosynthetic enzymes are very stable. We identified Fbx22 and SumO as HapX interactors and, in agreement, HapX post-translational modifications including ubiquitination of lysine¹⁶¹, sumoylation of lysine²⁴² and phosphorylation of threonine³¹⁹. All three modifications were enriched in the immediate adaptation from iron-limiting to iron-replete conditions. Interfering with these post-translational modifications, either by point mutations or by inactivation, of Fbx22 or SumO, altered HapX degradation, heme biosynthesis and iron resistance to different extents. Consistent with the need to precisely regulate HapX protein levels, overexpression of hapX caused significant growth defects under iron sufficiency. Taken together, our results indicate that post-translational regulation of HapX is important to control iron homeostasis in A. fumigatus. Full article

(This article belongs to the Special Issue Transition Metals in the Host-Pathogen Interaction)

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20 pages, 3735 KiB

Open AccessArticle

Zn-Enhanced Asp-Rich Antimicrobial Peptides: N-Terminal Coordination by Zn(II) and Cu(II), Which Distinguishes Cu(II) Binding to Different Peptides

by Adriana Miller, Agnieszka Matera-Witkiewicz, Aleksandra Mikołajczyk, Joanna Wątły, Dean Wilcox, Danuta Witkowska and Magdalena Rowińska-Żyrek

Int. J. Mol. Sci. 2021, 22(13), 6971; https://doi.org/10.3390/ijms22136971 - 28 Jun 2021

Cited by 9 | Viewed by 2426

Abstract

The antimicrobial activity of surfactant-associated anionic peptides (SAAPs), which are isolated from the ovine pulmonary surfactant and are selective against the ovine pathogen Mannheimia haemolytica, is strongly enhanced in the presence of Zn(II) ions. Both calorimetry and ITC measurements show that the [...] Read more.

The antimicrobial activity of surfactant-associated anionic peptides (SAAPs), which are isolated from the ovine pulmonary surfactant and are selective against the ovine pathogen Mannheimia haemolytica, is strongly enhanced in the presence of Zn(II) ions. Both calorimetry and ITC measurements show that the unique Asp-only peptide SAAP3 (DDDDDDD) and its analogs SAAP2 (GDDDDDD) and SAAP6 (GADDDDD) have a similar micromolar affinity for Zn(II), which binds to the N-terminal amine and Asp carboxylates in a net entropically-driven process. All three peptides also bind Cu(II) with a net entropically-driven process but with higher affinity than they bind Zn(II) and coordination that involves the N-terminal amine and deprotonated amides as the pH increases. The parent SAAP3 binds Cu(II) with the highest affinity; however, as shown with potentiometry and absorption, CD and EPR spectroscopy, Asp residues in the first and/or second positions distinguish Cu(II) binding to SAAP3 and SAAP2 from their binding to SAAP6, decreasing the Cu(II) Lewis acidity and suppressing its square planar amide coordination by two pH units. We also show that these metal ions do not stabilize a membrane disrupting ability nor do they induce the antimicrobial activity of these peptides against a panel of human pathogens. Full article

(This article belongs to the Special Issue Transition Metals in the Host-Pathogen Interaction)

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15 pages, 2110 KiB

Open AccessArticle

The Iron Chelator Desferrioxamine Increases the Efficacy of Bedaquiline in Primary Human Macrophages Infected with BCG

by Christina Cahill, Fiona O’Connell, Karl M. Gogan, Donal J. Cox, Sharee A. Basdeo, Jacintha O’Sullivan, Stephen V. Gordon, Joseph Keane and James J. Phelan

Int. J. Mol. Sci. 2021, 22(6), 2938; https://doi.org/10.3390/ijms22062938 - 13 Mar 2021

Cited by 5 | Viewed by 4466

Abstract

For over 50 years, patients with drug-sensitive and drug-resistant tuberculosis have undergone long, arduous, and complex treatment processes with several antimicrobials. With the prevalence of drug-resistant strains on the rise and new therapies for tuberculosis urgently required, we assessed whether manipulating iron levels [...] Read more.

For over 50 years, patients with drug-sensitive and drug-resistant tuberculosis have undergone long, arduous, and complex treatment processes with several antimicrobials. With the prevalence of drug-resistant strains on the rise and new therapies for tuberculosis urgently required, we assessed whether manipulating iron levels in macrophages infected with mycobacteria offered some insight into improving current antimicrobials that are used to treat drug-resistant tuberculosis. We investigated if the iron chelator, desferrioxamine, can support the function of human macrophages treated with an array of second-line antimicrobials, including moxifloxacin, bedaquiline, amikacin, clofazimine, linezolid and cycloserine. Primary human monocyte-derived macrophages were infected with Bacillus Calmette-Guérin (BCG), which is pyrazinamide-resistant, and concomitantly treated for 5 days with desferrioxamine in combination with each one of the second-line tuberculosis antimicrobials. Our data indicate that desferrioxamine used as an adjunctive treatment to bedaquiline significantly reduced the bacterial load in human macrophages infected with BCG. Our findings also reveal a link between enhanced bactericidal activity and increases in specific cytokines, as the addition of desferrioxamine increased levels of IFN-γ, IL-6, and IL-1β in BCG-infected human monocyte-derived macrophages (hMDMs) treated with bedaquiline. These results provide insight, and an in vitro proof-of-concept, that iron chelators may prove an effective adjunctive therapy in combination with current tuberculosis antimicrobials. Full article

(This article belongs to the Special Issue Transition Metals in the Host-Pathogen Interaction)

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16 pages, 2069 KiB

Open AccessArticle

The Esterase PfeE, the Achilles’ Heel in the Battle for Iron between Pseudomonas aeruginosa and Escherichia coli

by Véronique Gasser, Laurianne Kuhn, Thibaut Hubert, Laurent Aussel, Philippe Hammann and Isabelle J. Schalk

Int. J. Mol. Sci. 2021, 22(6), 2814; https://doi.org/10.3390/ijms22062814 - 10 Mar 2021

Cited by 12 | Viewed by 2657

Abstract

Bacteria access iron, a key nutrient, by producing siderophores or using siderophores produced by other microorganisms. The pathogen Pseudomonas aeruginosa produces two siderophores but is also able to pirate enterobactin (ENT), the siderophore produced by Escherichia coli. ENT-Fe complexes are imported across [...] Read more.

Bacteria access iron, a key nutrient, by producing siderophores or using siderophores produced by other microorganisms. The pathogen Pseudomonas aeruginosa produces two siderophores but is also able to pirate enterobactin (ENT), the siderophore produced by Escherichia coli. ENT-Fe complexes are imported across the outer membrane of P. aeruginosa by the two outer membrane transporters PfeA and PirA. Iron is released from ENT in the P. aeruginosa periplasm by hydrolysis of ENT by the esterase PfeE. We show here that pfeE gene deletion renders P. aeruginosa unable to grow in the presence of ENT because it is unable to access iron via this siderophore. Two-species co-cultures under iron-restricted conditions show that P. aeruginosa strongly represses the growth of E. coli as long it is able to produce its own siderophores. Both strains are present in similar proportions in the culture as long as the siderophore-deficient P. aeruginosa strain is able to use ENT produced by E. coli to access iron. If pfeE is deleted, E. coli has the upper hand in the culture and P. aeruginosa growth is repressed. Overall, these data show that PfeE is the Achilles’ heel of P. aeruginosa in communities with bacteria producing ENT. Full article

(This article belongs to the Special Issue Transition Metals in the Host-Pathogen Interaction)

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13 pages, 3323 KiB

Open AccessArticle

Identification of Active Site Residues of the Siderophore Synthesis Enzyme PvdF and Evidence for Interaction of PvdF with a Substrate-Providing Enzyme

by Priya Philem, Torsten Kleffmann, Sinan Gai, Bill C. Hawkins, Sigurd M. Wilbanks and Iain L. Lamont

Int. J. Mol. Sci. 2021, 22(4), 2211; https://doi.org/10.3390/ijms22042211 - 23 Feb 2021

Cited by 3 | Viewed by 2284

Abstract

The problematic opportunistic pathogen Pseudomonas aeruginosa secretes a siderophore, pyoverdine. Pyoverdine scavenges iron needed by the bacteria for growth and for pathogenicity in a range of different infection models. PvdF, a hydroxyornithine transformylase enzyme, is essential for pyoverdine synthesis, catalysing synthesis of formylhydroxyornithine [...] Read more.

The problematic opportunistic pathogen Pseudomonas aeruginosa secretes a siderophore, pyoverdine. Pyoverdine scavenges iron needed by the bacteria for growth and for pathogenicity in a range of different infection models. PvdF, a hydroxyornithine transformylase enzyme, is essential for pyoverdine synthesis, catalysing synthesis of formylhydroxyornithine (fOHOrn) that forms part of the pyoverdine molecule and provides iron-chelating hydroxamate ligands. Using a mass spectrometry assay, we confirm that purified PvdF catalyses synthesis of fOHOrn from hydroxyornithine and formyltetrahydrofolate substrates. Site directed mutagenesis was carried out to investigate amino acid residues predicted to be required for enzymatic activity. Enzyme variants were assayed for activity in vitro and also in vivo, through measuring their ability to restore pyoverdine production to a pvdF mutant strain. Variants at two putative catalytic residues N168 and H170 greatly reduced enzymatic activity in vivo though did not abolish activity in vitro. Change of a third residue D229 abolished activity both in vivo and in vitro. A change predicted to block entry of N¹⁰-formyltetrahydrofolate (fTHF) to the active site also abolished activity both in vitro and in vivo. A co-purification assay showed that PvdF binds to an enzyme PvdA that catalyses synthesis of hydroxyornithine, with this interaction likely to increase the efficiency of fOHOrn synthesis. Our findings advance understanding of how P. aeruginosa synthesises pyoverdine, a key factor in host–pathogen interactions. Full article

(This article belongs to the Special Issue Transition Metals in the Host-Pathogen Interaction)

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Review

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19 pages, 909 KiB

Open AccessReview

Recent Advances in Iron Chelation and Gallium-Based Therapies for Antibiotic Resistant Bacterial Infections

by Víctor Vinuesa and Michael J. McConnell

Int. J. Mol. Sci. 2021, 22(6), 2876; https://doi.org/10.3390/ijms22062876 - 12 Mar 2021

Cited by 31 | Viewed by 5347

Abstract

Iron is essential for multiple bacterial processes and is thus required for host colonization and infection. The antimicrobial activity of multiple iron chelators and gallium-based therapies against different bacterial species has been characterized in preclinical studies. In this review, we provide a synthesis [...] Read more.

Iron is essential for multiple bacterial processes and is thus required for host colonization and infection. The antimicrobial activity of multiple iron chelators and gallium-based therapies against different bacterial species has been characterized in preclinical studies. In this review, we provide a synthesis of studies characterizing the antimicrobial activity of the major classes of iron chelators (hydroxamates, aminocarboxylates and hydroxypyridinones) and gallium compounds. Special emphasis is placed on recent in-vitro and in-vivo studies with the novel iron chelator DIBI. Limitations associated with iron chelation and gallium-based therapies are presented, with emphasis on limitations of preclinical models, lack of understanding regarding mechanisms of action, and potential host toxicity. Collectively, these studies demonstrate potential for iron chelators and gallium to be used as antimicrobial agents, particularly in combination with existing antibiotics. Additional studies are needed in order to characterize the activity of these compounds under physiologic conditions and address potential limitations associated with their clinical use as antimicrobial agents. Full article

(This article belongs to the Special Issue Transition Metals in the Host-Pathogen Interaction)

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