Enterobacteria secrete an inhibitor of Pseudomonas virulence during clinical bacteriuria

Ohlemacher, Shannon I.; Giblin, Daryl; d’Avignon, D. André; Stapleton, Ann E.; Trautner, Barbara W.; Henderson, Jeffrey P.

doi:10.1172/jci92464

Cited by 34 publications

(56 citation statements)

References 90 publications

(129 reference statements)

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“…The LC separation was performed with an Ascentis Express phenyl-hexyl column (100 ϫ 2.1 mm, 2.7 M; Sigma) and the mobile phases: A ϭ HPLC-grade water ϩ 0.1% (v/v) formic acid (Sigma) and B ϭ 90% acetonitrile (EMD Millipore) ϩ 0.1% (v/v) formic acid. All LC and MS settings were the same as described previously (57). Ybt levels were assessed by taking the peak area ratio of the native isotope Fe-Ybt to the internal standard Fe-13 C-Ybt.…”

Section: Ybt Detection In Bacterial Culturementioning

confidence: 99%

YbtT is a low-specificity type II thioesterase that maintains production of the metallophore yersiniabactin in pathogenic enterobacteria

Ohlemacher

Kober

et al. 2018

Journal of Biological Chemistry

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Edited by Ruma BanerjeeClinical isolates of Yersinia, Klebsiella, and Escherichia coli frequently secrete the small molecule metallophore yersiniabactin (Ybt), which passivates and scavenges transition metals during human infections. YbtT is encoded within the Ybt biosynthetic operon and is critical for full Ybt production in bacteria. However, its biosynthetic function has been unclear because it is not essential for Ybt production by the in vitro reconstituted nonribosomal peptide synthetase/polyketide synthase (NRPS/ PKS) pathway. Here, we report the structural and biochemical characterization of YbtT. YbtT structures at 1.4 -1.9 Å resolution possess a serine hydrolase catalytic triad and an associated substrate chamber with features similar to those previously reported for low-specificity type II thioesterases (TEIIs). We found that YbtT interacts with the two major Ybt biosynthetic proteins, HMWP1 (high-molecular-weight protein 1) and HMWP2 (high-molecular-weight protein 2), and hydrolyzes a variety of aromatic and acyl groups from their phosphopantetheinylated carrier protein domains. In vivo YbtT titration in uropathogenic E. coli revealed a distinct optimum for Ybt production consistent with a tradeoff between clearing both stalled inhibitory intermediates and productive Ybt precursors from HMWP1 and HMWP2. These results are consistent with a 6 The abbreviations used are:

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Section: Ybt Detection In Bacterial Culturementioning

confidence: 99%

YbtT is a low-specificity type II thioesterase that maintains production of the metallophore yersiniabactin in pathogenic enterobacteria

Ohlemacher

Kober

et al. 2018

Journal of Biological Chemistry

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“…Clinical enterobacterial isolates often possess additional, non-essential, virulenceassociated genes. Prominent among these is the Yersinia high pathogenicity island (HPI), which encodes the biosynthetic machinery to make the specialized metabolites yersiniabactin (Ybt) and escherichelin (2). Direct mass spectrometric detection of urinary Ybt in UTI patients, serological markers, transcriptional signatures, and experimental infection models all indicate active expression of Yersinia HPI proteins during UTI pathogenesis (3)(4)(5)(6)(7).…”

mentioning

confidence: 99%

Uropathogenic enterobacteria use the yersiniabactin metallophore system to acquire nickel

Robinson¹,

Lowe²,

Koh³

et al. 2018

Journal of Biological Chemistry

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Invasive gram-negative bacteria often express multiple virulence-associated metal ion chelators to combat host-mediated metal deficiencies. Escherichia coli, Klebsiella, and Yersinia pestis isolates encoding the Yersinia High Pathogenicity Island (HPI) secrete yersiniabactin (Ybt), a metallophore originally shown to chelate iron ions during infection. However, our recent demonstration that Ybt also scavenges copper ions during infection led us to question whether it might be capable of retrieving other metals as well. Here, we find that uropathogenic E. coli also use Ybt to bind extracellular nickel ions. Using quantitative mass spectrometry, we show that the canonical metal-Ybt import pathway internalizes the resulting Ni-Ybt complexes, extracts the nickel, and releases metal-free Ybt back to the extracellular space. We find that E. coli and Klebsiella direct the nickel liberated from this pathway to intracellular nickel enzymes. Thus, Ybt may provide access to nickel that is inaccessible to the conserved NikABCDE permease system. Nickel should be considered alongside iron and copper as a plausible substrate for Ybt-mediated metal import by enterobacteria during human infections.E. coli and related enterobacteria are the predominant cause of human urinary tract infections (UTIs) and contribute substantially to the worldwide rise in antibiotic-resistant infections (1). Clinical enterobacterial isolates often possess additional, non-essential, virulenceassociated genes. Prominent among these is the Yersinia high pathogenicity island (HPI), which encodes the biosynthetic machinery to make the specialized metabolites yersiniabactin (Ybt) and escherichelin (2). Direct mass spectrometric detection of urinary Ybt in UTI patients, serological markers, transcriptional signatures, and experimental infection models all indicate active expression of Yersinia HPI proteins during UTI pathogenesis (3-7).Although initially understood as a siderophore-a chelator that binds Fe(III) for bacterial use-Ybt has recently been appreciated to exhibit a broader metal ion binding repertoire. Copper-Ybt complexes were observed in E. coli UTI patients and were connected to protection of E. coli from copper toxicity (7), an example of biological metal passivation. Because copper is an important nutrient, complete sequestration of copper ions by Ybt could starve uropathogenic E. coli (UPEC) of copper. However, UPEC retain nutritional access to Ybt-bound copper and iron by importing the metal-Ybt complexes in a controlled manner, extracting the metal, and using it to support metal-dependent cellular functions (8). These findings implicate Ybt as an agent of nutritional passivation, a biological strategy in which metal ion toxicity is minimized Ybt-mediated nickel acquisition 2 while nutritional access is preserved. In this manner, Ybt acts as an extracellular metal ion sink, with subsequent entry into the cell occurring as a controlled process. Whether this nutritional passivation activity of Ybt extends to biological metal ions beyon...

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“…A recent study showed that Ent-Cipro, a synthetic siderophore-antibiotic conjugate based on the native Ent (enterobactin, a kind of siderophore) platform affords targeted antibacterial activity against Escherichia coli strains that express the pathogen-associated IroA gene cluster (Neumann et al, 2018). Furthermore, yersiniabactin and salmochelin produced by E. coli strains have been proven to cause infection in UTIs by previous experiments, and lead to new antibiotics against these two siderophores as a potential strategy to prevent and treat UTIs (Henderson et al, 2009;Su et al, 2016;Ohlemacher et al, 2017). Furthermore, Rakin et al (2012) demonstrated that there are several siderophore iron-scavenging systems apart from Ybt in another highly virulent genus-Yersinia.…”

Section: Innovative Applications Of Siderophores In Deciphering Tmentioning

confidence: 99%

Mass spectrometry and associated technologies delineate the advantageously biomedical capacity of siderophores in different pathogenic contexts

Luo

Guo

et al. 2018

Mass Spectrometry Reviews

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Siderophores are chemically diverse small molecules produced by microorganisms for chelation of irons to maintain their survival and govern some important biological functions, especially those cause that infections in hosts. Still, siderophores can offer new insight into a better understanding of the diagnosis and treatments of infectious diseases from the siderophore biosynthesis and regulation perspective. Thus, this review aims to summarize the biomedical value and applicability of siderophores in pathogenic contexts by briefly reviewing mass spectrometry (MS)-based chemical biology and translational applications that involve diagnosis, pathogenesis, and therapeutic discovery for a variety of infectious conditions caused by different pathogens. We highlight the advantages and disadvantages of siderophore discovery and applications in pathogenic contexts. Finally, we propose a panel of new and promising strategy as precision-modification metabolomics method, to rapidly advance the discovery of and translational innovations pertaining to these value compounds in broad biomedical niches. © 2018 Wiley Periodicals, Inc. Mass Spec Rev XX:XX-XX, 2018.

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Enterobacteria secrete an inhibitor of Pseudomonas virulence during clinical bacteriuria

Cited by 34 publications

References 90 publications

YbtT is a low-specificity type II thioesterase that maintains production of the metallophore yersiniabactin in pathogenic enterobacteria

YbtT is a low-specificity type II thioesterase that maintains production of the metallophore yersiniabactin in pathogenic enterobacteria

Uropathogenic enterobacteria use the yersiniabactin metallophore system to acquire nickel

Mass spectrometry and associated technologies delineate the advantageously biomedical capacity of siderophores in different pathogenic contexts

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