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 family is presented in which ano‐rectal malformation and feautures common to Alport Syndrome appear to be present in three generations. The possiblity of a new syndrome bassed on a single gene defect is discussed.

Metal ions can play dual roles as nutrients and toxins in the interaction between bacteria and their environments. E. coli isolates associated with urinary tract infections (UTIs) deploy siderophores, small molecule chelators defined by their ability to competitively bind iron(III) and deliver it to the cell. Yersiniabactin (Ybt) is a virulence‐associated siderophore of uropathogenic E. coli (UPEC) and was recently appreciated to also bind copper during UTIs in humans, forming Cu(II)‐Ybt complexes. Copper binding by Ybt was found to protect E. coli from copper toxicity and also to mediate controlled copper import for nutritional purposes. We have termed this process nutritional passivation. Ni(II) is generally less abundant than copper but is also a nutrient for E. coli with the potential for toxicity. We show here that the Ybt system of UPEC engages in an analogous nutritional passivation activity with Ni(II). Ybt passivates Ni(II) ions, protecting against Ni(II) toxicity in vitro. We also observe that UPEC can use Ni(II)‐Ybt as a nutrient source for nickel. Using quantitative LC‐MS/MS and isotope labeling, we detect import of Ni(II)‐Ybt and dissociation of the nickel, providing a nickel source for cellular enzymes. The metal‐free Ybt is secreted back outside of the cell to bind other metal ions. These findings broaden the spectrum of Ybt activity, reinforcing its value to UPEC as a true metallophore, capable of binding and importing not only iron, but also copper and nickel.Support or Funding InformationJ.P.H. acknowledges National Institute of Diabetes and Digestive and Kidney Diseases grant R01DK099534. A.E.R. was supported by the Mr. and Mrs. Spencer T. Olin Fellowship for Women in Graduate Study.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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