Iron is a versatile redox-active catalyst and a required cofactor within a diverse array of biological processes. To almost all organisms, iron is both essential and potentially toxic, where homeostatic concentrations must be stringently maintained. Within the iron-restricted host, the survival and proliferation of microbial invaders is contingent upon exploiting the host iron pool. Bacteria express a multitude of complex, and often redundant means of acquiring iron, including surface-associated heme-uptake pathways, high affinity iron-scavenging siderophores and transporters of free inorganic iron. Within the last decade, our understanding of iron acquisition by Gram-positive pathogens has expanded substantively, from the discovery of the iron-regulated surface-determinant pathway and numerous unique siderophores through to the detailed elucidation of heme-iron extraction, and heme and siderophore coordination and transfer. This review provides a comprehensive summary of the iron acquisition strategies of notorious Gram-positive pathogens and highlights how both conserved and distinct tactics for acquiring iron contribute to the pathophysiology of these bacteria. Further, a focus on recent structural and mechanistic studies details how these iron acquisition systems may be exploited in the development of novel therapeutics.
Serine hydrolases play diverse roles in regulating host-pathogen interactions in a number of organisms, yet few have been characterized in the human pathogen Staphylococcus aureus. Here, we describe a chemical proteomic screen that identified 10 previously uncharacterized S. aureus serine hydrolases that mostly lack human homologues. We termed these enzymes Fluorophosphonate-binding hydrolases (FphA-J). One hydrolase, FphB, can process short fatty acid esters, exhibits increased activity in response to host cell factors, is located predominantly on the bacterial cell surface in a subset of cells, and is concentrated in the division septum. Genetic disruption of the fphB gene confirms that the enzyme is dispensable for bacterial growth in culture but crucial for establishing infection in distinct sites in vivo. A selective small molecule inhibitor of FphB effectively reduces infectivity in vivo, suggesting that it may be a viable therapeutic target for the treatment or management of Staphylococcus infections.
Acinetobacter baumannii is an emerging pathogen that poses a global health threat due to a lack of therapeutic options for treating drug-resistant strains. In addition to acquiring resistance to last-resort antibiotics, the success of A . baumannii is partially due to its ability to effectively compete with the host for essential metals. Iron is fundamental in shaping host-pathogen interactions, where the host restricts availability of this nutrient in an effort to curtail bacterial proliferation. To circumvent restriction, pathogens possess numerous mechanisms to obtain iron, including through the use of iron-scavenging siderophores. A . baumannii elaborates up to ten distinct siderophores, encoded from three different loci: acinetobactin and pre-acinetobactin (collectively, acinetobactin), baumannoferrins A and B, and fimsbactins A-F. The expression of multiple siderophores is common amongst bacterial pathogens and often linked to virulence, yet the collective contribution of these siderophores to A . baumannii survival and pathogenesis has not been investigated. Here we begin dissecting functional redundancy in the siderophore-based iron acquisition pathways of A . baumannii . Excess iron inhibits overall siderophore production by the bacterium, and the siderophore-associated loci are uniformly upregulated during iron restriction in vitro and in vivo . Further, disrupting all of the siderophore biosynthetic pathways is necessary to drastically reduce total siderophore production by A . baumannii , together suggesting a high degree of functional redundancy between the metabolites. By contrast, inactivation of acinetobactin biosynthesis alone impairs growth on human serum, transferrin, and lactoferrin, and severely attenuates survival of A . baumannii in a murine bacteremia model. These results suggest that whilst A . baumannii synthesizes multiple iron chelators, acinetobactin is critical to supporting growth of the pathogen on host iron sources. Given the acinetobactin locus is highly conserved and required for virulence of A . baumannii , designing therapeutics targeting the biosynthesis and/or transport of this siderophore may represent an effective means of combating this pathogen.
Staphylococcus aureus is a Gram-positive pathogen responsible for tremendous morbidity and mortality. As with most bacteria, S. aureus requires iron to cause disease, and it can acquire iron from host hemoglobin. The current model for staphylococcal hemoglobin-iron acquisition proposes that S. aureus binds hemoglobin through the surface-exposed hemoglobin receptor IsdB. IsdB removes heme from bound hemoglobin and transfers this cofactor to other proteins of the Isd system, which import and degrade heme to release iron in the cytoplasm. Here we demonstrate that the individual components of the Isd system are required for growth on low nanomolar concentrations of hemoglobin as a sole source of iron. An in-depth study of hemoglobin binding by IsdB revealed key residues that are required for hemoglobin binding. Further, we show that these residues are necessary for heme extraction from hemoglobin and growth on hemoglobin as a sole iron source. These processes are found to contribute to the pathogenicity of S. aureus in a murine model of infection. Together these results build on the model for Isd-mediated hemoglobin binding and heme-iron acquisition during the pathogenesis of S. aureus infection.
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.
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