Iron is an essential micronutrient for both microbes and humans alike. For well over half a century we have known that this element, in particular, plays a pivotal role in health and disease and, most especially, in shaping host-pathogen interactions. Intracellular iron concentrations serve as a critical signal in regulating the expression not only of high-affinity iron acquisition systems in bacteria, but also of toxins and other noted virulence factors produced by some major human pathogens. While we now are aware of many strategies that the host has devised to sequester iron from invading microbes, there are as many if not more sophisticated mechanisms by which successful pathogens overcome nutritional immunity imposed by the host. This review discusses some of the essential components of iron sequestration and scavenging mechanisms of the host, as well as representative Gram-negative and Gram-positive pathogens, and highlights recent advances in the field. Last, we address how the iron acquisition strategies of pathogenic bacteria may be exploited for the development of novel prophylactics or antimicrobials.

Staphylococcus aureus is a significant cause of human infection. Here, we demonstrate that mutations in the transcriptional repressor of purine biosynthesis, purR, enhance the pathogenic potential of S. aureus. Indeed, systemic infection with purR mutants causes accelerated mortality in mice, which is due to aberrant up-regulation of fibronectin binding proteins (FnBPs). Remarkably, purR mutations can arise upon exposure of S. aureus to stress, such as an intact immune system. In humans, naturally occurring anti-FnBP antibodies exist that, while not protective against recurrent S. aureus infection, ostensibly protect against hypervirulent S. aureus infections. Vaccination studies support this notion, where anti-Fnb antibodies in mice protect against purR hypervirulence. These findings provide a novel link between purine metabolism and virulence in S. aureus.

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Staphylococcus aureus possesses a multitude of mechanisms by which it can obtain iron during growth under iron starvation conditions. It expresses an effective heme acquisition system (the iron-regulated surface determinant system), it produces two carboxylate-type siderophores staphyloferrin A and staphyloferrin B (SB), and it expresses transporters for many other siderophores that it does not synthesize. The ferric uptake regulator protein regulates expression of genes encoding all of these systems. Mechanisms of fine-tuning expression of ironregulated genes, beyond simple iron regulation via ferric uptake regulator, have not been uncovered in this organism. Here, we identify the ninth gene of the sbn operon, sbnI, as encoding a ParB/Spo0J-like protein that is required for expression of genes in the sbn operon from sbnD onward. Expression of sbnD-I is drastically decreased in an sbnI mutant, and the mutant does not synthesize detectable SB during early phases of growth. Thus, SB-mediated iron acquisition is impaired in an sbnI mutant strain. We show that the protein forms dimers and tetramers in solution and binds to DNA within the sbnC coding region. Moreover, we show that SbnI binds heme and that heme-bound SbnI does not bind DNA. Finally, we show that providing exogenous heme to S. aureus growing in an iron-free medium results in delayed synthesis of SB. This is the first study in S. aureus that identifies a DNA-binding regulatory protein that senses heme to control gene expression for siderophore synthesis.

Edited by F. Peter Guengerich Staphylococcus aureus infection relies on iron acquisition from its host. S. aureus takes up iron through heme uptake by the iron-responsive surface determinant (Isd) system and by the production of iron-scavenging siderophores. Staphyloferrin B (SB) is a siderophore produced by the 9-gene sbn gene cluster for SB biosynthesis and efflux. Recently, the ninth gene product, SbnI, was determined to be a free L-serine kinase that produces O-phospho-L-serine (OPS), a substrate for SB biosynthesis. Previous studies have also characterized SbnI as a DNA-binding regulatory protein that senses heme to control sbn gene expression for SB synthesis. Here, we present crystal structures at 1.9-2.1 Å resolution of a SbnI homolog from Staphylococcus pseudintermedius (SpSbnI) in both apo form and in complex with ADP, a product of the kinase reaction; the latter confirmed the active-site location. The structures revealed that SpSbnI forms a dimer through C-terminal domain swapping and a dimer of dimers through intermolecular disulfide formation. Heme binding had only a modest effect on SbnI enzymatic activity, suggesting that its two functions are independent and structurally distinct. We identified a heme-binding site and observed catalytic heme transfer between a heme-degrading protein of the Isd system, IsdI, and SbnI. These findings support the notion that SbnI has a bifunctional role contributing precursor OPS to SB synthesis and directly sensing heme to control expression of the sbn locus. We propose that heme transfer from IsdI to SbnI enables S. aureus to control iron source preference according to the sources available in the environment. Staphylococcus aureus is a prominent cause of infectious disease in humans (1, 2). Frequently associated with minor skin This work was supported by the Canadian Institutes of Health Research (CIHR) Grants MOP-49597 (to M. E. P. M.) and 374480 (to D. E. H.) and by the Natural Sciences and Engineering Research Council (NSERC) through Discovery Grant 0037-215 (to M. J. S.) and Postdoctoral Scholarships Doctoral (to M. M. V. and T. B. P.), and infrastructure support for structural biology was provided by the Canadian Foundation for Innovation (to M. E. P. M.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This article contains Figs. S1-S9 and Tables S1-S3. The atomic coordinates and structure factors (codes 5UJD and 6NR6) have been deposited in the Protein Data Bank (http://wwpdb.org/).