Recent developments in understanding the iron acquisition strategies of gram positive pathogens

Abstract

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.

Iron acquisition in the cystic fibrosis lung and potential for novel therapeutic strategies

“…Staphylococcus aureus can acquire iron using a variety of xenosiderophores (Table 1), including hydroxamate siderophores, which itself cannot produce, using the conserved ferric hydroxamate uptake system Fhu (Sebulsky et al, 2003(Sebulsky et al, , 2004, and catecholate xenosiderophores through the highly conserved staphylococcal siderophore ATP-binding cassette (ABC) transporter SstABCD (Beasley et al, 2011). Iron acquisition strategies of Gram-positive pathogens including Staphylococcus aureus are the subject of a recent review by Sheldon & Heinrichs (2015).…”

Chemical Synthesis of Staphyloferrin B Affords Insight into the Molecular Structure, Iron Chelation, and Biological Activity of a Polycarboxylate Siderophore Deployed by the Human Pathogen Staphylococcus aureus

“…[1][2][3] Deciphering the numerous strategies that S. aureus employs to colonize a host and cause infection at the molecular level is important for developing new therapeutics to treat S. aureus infections. 2 Iron is an essential nutrient for almost all organisms, [4][5][6] and S. aureus must acquire this element in the host to colonize and cause infection. 7,8 One strategy that S. aureus employs to acquire iron involves the biosynthesis and utilization of siderophores, 9,10 which are small-molecule iron(III) chelators produced by bacteria confronted with conditions of iron limitation.…”

The Staphylococcus aureus Protein IsdH Inhibits Host Hemoglobin Scavenging to Promote Heme Acquisition by the Pathogen

“…The functions of most of these proteins have been elucidated: extraction of heme is achieved by the two bacterial surface-exposed Hb-receptors, IsdB and IsdH; transport of heme across the bacterial cell wall and plasma membrane is performed by IsdA and IsdC together with the membrane protein IsdEF complex; and the heme oxygenase enzymes IsdG and IsdH, located in the cytoplasm, finally cleave the porphyrin ring (reviewed in Ref. 7). Although the role of Isd proteins in the sequestering of iron from free Hb is well understood, this may not apply to the situation in the blood where extracellular Hb is found in complex with Hp.…”