Chemical and Biological Aspects of Nutritional Immunity—Perspectives for New Anti‐Infectives that Target Iron Uptake Systems

Bilitewski, Ursula; Blodgett, Joshua A. V.; Duhme‐Klair, Anne‐Kathrin; Dallavalle, Sabrina; Routledge, Anne; Schobert, Rainer

doi:10.1002/anie.201701586

Cited by 59 publications

(75 citation statements)

References 212 publications

(322 reference statements)

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“…It is essential that bacteria acquire iron(III) from their environment; however, iron(III) is unable to passively diffuse through bacterial membranes. Bacteria synthesize and secrete siderophore molecules with high binding affinities into their surrounding environment to sequester iron(III).…”

Section: Phenazine Antibiotics: Inspiration For the Discovery Of New mentioning

confidence: 99%

Phenazine Antibiotic‐Inspired Discovery of Bacterial Biofilm‐Eradicating Agents

2019

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Bacterial biofilms are surface‐attached communities of slow‐growing and non‐replicating persister cells that demonstrate high levels of antibiotic tolerance. Biofilms occur in nearly 80 % of infections and present unique challenges to our current arsenal of antibiotic therapies, all of which were initially discovered for their abilities to target rapidly dividing, free‐floating planktonic bacteria. Bacterial biofilms are credited as the underlying cause of chronic and recurring bacterial infections. Innovative approaches are required to identify new small molecules that operate through bacterial growth‐independent mechanisms to effectively eradicate biofilms. One source of inspiration comes from within the lungs of young cystic fibrosis (CF) patients, who often endure persistent Staphylococcus aureus infections. As these CF patients age, Pseudomonas aeruginosa co‐infects the lungs and utilizes phenazine antibiotics to eradicate the established S. aureus infection. Our group has taken a special interest in this microbial competition strategy and we are investigating the potential of phenazine antibiotic‐inspired compounds and synthetic analogues thereof to eradicate persistent bacterial biofilms. To discover new biofilm‐eradicating agents, we have established an interdisciplinary research program involving synthetic medicinal chemistry, microbiology and molecular biology. From these efforts, we have identified a series of halogenated phenazines (HPs) that potently eradicate bacterial biofilms, and future work aims to translate these preliminary findings into ground‐breaking clinical advances for the treatment of persistent biofilm infections.

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Section: Phenazine Antibiotics: Inspiration For the Discovery Of New mentioning

confidence: 99%

Phenazine Antibiotic‐Inspired Discovery of Bacterial Biofilm‐Eradicating Agents

2019

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“…[26,27] Other MRSA biofilm gene clusters with changes in expression profiles due to HP-14 include: spl (serine proteases; [28] activated), opp (oligopeptide transporters; [29] activated), gap (glycolysis; [30] inhibited), arc (arginine deiminase; [31] inhibited), ure (urease; [32] inhibited), hem (heme biosynthesis; [33] inhibited), and an uncharacterized gene cluster containing dnaC (DNA synthesis and repair; [34] inhibited; see Figures 1 and 2 in the Supporting Information). Several gene clusters with unknown functions or lower levels of activation/inhibition in response to HP-14 are presented in the Supporting Information (for WoPPER details, see Tables 6 and 7).…”

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confidence: 99%

“…ABC transporters are crucial transport systems for nutrient uptake by bacteria, [36] including iron. [27] Altered genes expressed in the ABC transporter category include sirAB , fhuBC , isdEF , and oppDF . Overall, this KEGG analysis leads us to conclude that metabolic pathways and ABC transporters are important for MRSA biofilm survival, as HP-14 significantly impacts genes involved in these functions.…”

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confidence: 99%

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Transcript Profiling of MRSA Biofilms Treated with a Halogenated Phenazine Eradicating Agent: A Platform for Defining Cellular Targets and Pathways Critical to Biofilm Survival

et al. 2018

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Bacterial biofilms are surface-attached communities of non-replicating bacteria innately tolerant to antibiotics. Biofilms display differential gene expression profiles and physiologies as compared to their planktonic counterparts; however, their biology remains largely unknown. In this study, we used a halogenated phenazine (HP) biofilm eradicator in transcript profiling experiments (RNA-seq) to define cellular targets and pathways critical to biofilm viability. WoPPER analysis with time-course validation (RT-qPCR) revealed that HP-14 induces rapid iron starvation in MRSA biofilms, as evident by the activation of iron-acquisition gene clusters in 1 hour. Serine proteases and oligopeptide transporters were also found to be up-regulated, whereas glycolysis, arginine deiminase, and urease gene clusters were down-regulated. KEGG analysis revealed that HP-14 impacts metabolic and ABC transporter functional pathways. These findings suggest that MRSA biofilm viability relies on iron homeostasis.

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“…Generally, reprogramming of lipocalins such as Scn offers an attractive strategy to scavenge stealth siderophores and, in this way, deprive bacteria of iron, a concept that might even be expanded to acquisition systems for other essential transition metals . Corresponding engineered lipocalins should be useful to treat bacterial infections as part of a therapeutic regimen, either alone, by complementing conventional antibiotics, or in combination with other antimicrobial compounds …”

Section: The Potential Of Engineered Lipocalins For Antibacterial Thementioning

confidence: 99%

Scavenging Bacterial Siderophores with Engineered Lipocalin Proteins as an Alternative Antimicrobial Strategy

Dauner

Skerra

2019

ChemBioChem

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Iron acquisition mediated by siderophores, high‐affinity chelators for which bacteria have evolved specific synthesis and uptake mechanisms, plays a crucial role in microbiology and in host–pathogen interactions. In the ongoing fight against bacterial infections, this area has attracted biomedical interest. Beyond several approaches to interfere with siderophore‐mediated iron uptake from medicinal and immunochemistry, the development of high‐affinity protein scavengers that tightly complex the siderophores produced by pathogenic bacteria has appeared as a novel strategy. Such binding proteins have been engineered based on siderocalin—also known as lipocalin 2—an endogenous human scavenger of enterobactin and bacillibactin that controls the systemic spreading of commensal bacteria such as Escherichia coli. By using combinatorial protein design, siderocalin was reshaped to bind several siderophores from Pseudomonas aeruginosa and, in particular, petrobactin from Bacillus anthracis, none of which is recognized by the natural protein. Such engineered versions of siderocalin effectively suppress the growth of corresponding pathogenic bacteria by depriving them of their iron supply and offer the potential to complement antibiotic therapy in situations of acute or persistent infection.

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Chemical and Biological Aspects of Nutritional Immunity—Perspectives for New Anti‐Infectives that Target Iron Uptake Systems

Cited by 59 publications

References 212 publications

Phenazine Antibiotic‐Inspired Discovery of Bacterial Biofilm‐Eradicating Agents

Phenazine Antibiotic‐Inspired Discovery of Bacterial Biofilm‐Eradicating Agents

Transcript Profiling of MRSA Biofilms Treated with a Halogenated Phenazine Eradicating Agent: A Platform for Defining Cellular Targets and Pathways Critical to Biofilm Survival

Scavenging Bacterial Siderophores with Engineered Lipocalin Proteins as an Alternative Antimicrobial Strategy

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