Transition metals such as iron, manganese, copper, and zinc are essential trace elements for all kingdoms of life. Due to their redox potential, transition metals can convert between divalent and trivalent states making them ideal to support enzymatic processes. Molecular iron is of major importance in this regard as it is essential for several central metabolic and cellular processes including glycolysis, oxidative decarboxylation, respiration, and DNA replication (Schaible and Kaufmann, 2004). Accordingly, appropriate acquisition of iron is essential for bacterial growth and this dependency is a major target for eukaryotic innate immune strategies to limit bacterial infections. Targeted depletion of human body fluids from trace metals effectively limits bacterial proliferation and is referred to as nutritional immunity (Murdoch and Skaar, 2022; Weinberg, 1975). To overcome host-induced iron starvation, bacterial pathogens have developed a range of strategies to acquire iron during infection (Sheldon et al., 2016). They can secrete siderophores, which possess sufficient affinity toward Fe³⁺ to extract the ion from host-chelating molecules (e.g. transferrin, lactoferrin) (Miethke and Marahiel, 2007). Staphylococcus aureus secretes the carboxylate-type siderophores staphyloferrin A (SA) and staphyloferrin B (SB), and their iron-saturated forms are acquired by the membrane-located HtsABC and SirABC systems, respectively (Beasley et al., 2009; Cheung et al., 2009). Additionally, S. aureus expresses systems for acquisition of siderophores produced by other bacterial species (xenosiderophores). The FhuBGCD₁D₂ system enables acquisition of hydroxamate-type siderophores (Sebulsky and Heinrichs, 2001) and the SstABCD system allows acquisition of iron-chelating molecules of the catecholate-type including xenosiderophores, but also human-derived catecholamine stress hormones like epinephrine, norepinephrine, or dopamine (Beasley et al., 2011). Moreover, the FeoAB transporter presumably allows acquisition of inorganic Fe²⁺(Sheldon and Heinrichs, 2015). In humans, much of the iron is bound to heme in hemoglobin (Hb), which can be released from erythrocytes by the action of cytolytic toxins (Cassat and Skaar, 2013; Spaan et al., 2015). A well-known mechanism for heme acquisition is the iron-regulated surface determinant (Isd) systems. This was first described for the invasive pathogen S. aureus (Mazmanian et al., 2003). Similar systems have since been identified in Staphylococcus lugdunensis (Heilbronner et al., 2016), Staphylococcus capitis, and Staphylococcus caprea (Sun et al., 2020) as well as in phylogenetically more distant Gram-positive pathogens such as Bacillus anthracis (Gat et al., 2008; Maresso et al., 2006), Bacillus cereus (Abi-Khalil et al., 2015), and Listeria monocytogenes (Klebba et al., 2012; Xiao et al., 2011). All Isd systems contain surface-anchored molecules to extract heme from host hemoproteins and to guide it over the cell wall to a membrane-located ATP-binding cassette (ABC) transporter. In the cytosol, the heme is degraded to release ionic iron. The Isd system of S. aureus is best studied (Sheldon and Heinrichs, 2015). Here, the cell wall-anchored proteins (CWAs) IsdB and IsdH bind Hb and Hb-haptoglobin complexes, respectively. Heme is removed from the hemoproteins by IsdA and IsdB and transferred to IsdC in the cell wall. Heme is then transferred to the heme-specific lipoprotein IsdE on the outer leaflet of the cell membrane. The permease IsdF functions as homodimer and transports heme into the cytosol. There, the two monooxygenases IsdG and IsdI release iron from heme.

The passage of heme across the cell wall of S. aureus has been studied in great detail. In contrast, the process of heme transport across the membrane remains somewhat undefined. Importantly, an ATPase is not encoded within the isd operon of S. aureus, raising the question of how the transport of heme is energized. Additionally, it is unclear if heme funneling across the cell wall demands the membrane transporter to be in a specific location within the liquid mosaic of the membrane to ensure effective passage of heme from the CWAs to the lipoprotein IsdE. It is increasingly recognized that bacterial membranes represent highly structured cellular compartments. In this regard, functional membrane microdomains (FMMs) have gained increasing attention in the recent years (Bach and Bramkamp, 2013; Bramkamp and Lopez, 2015; Farnoud et al., 2015; López and Kolter, 2010; Matsumoto et al., 2006; Yokoyama and Matsui, 2020). FMMs are specific domains in the bacterial membrane that, in the case of S. aureus, consist of the polyisoprenoid staphyloxanthin and its derivative lipids. An intrinsic characteristic of FMMs is the structural protein flotillin A (FloA) recruiting proteins to the FMMs and promoting their oligomerization (Bramkamp and Lopez, 2015; López and Kolter, 2010). FMMs have been shown to be crucial to coordinate diverse cellular functions in S. aureus. On one hand, they control activity of cell wall biosynthetic enzymes such as PBP2a and are essential for expression of resistance to β-lactam antibiotics in methicillin-resistant S. aureus (MRSA) (García-Fernández et al., 2017). On the other hand, several membrane-associated processes such as the secretion of type VII secretion effector proteins (Mielich-Süss et al., 2017) or the RNase Rny depend on FloA (Koch et al., 2017).

In this study, we have used bacterial two-hybrid assays to show direct interaction between the iron-responsive ATPase FhuC and the heme permease protein IsdF. Additionally, we have shown that Hb-dependent growth requires FhuC activity, suggesting that FhuC energizes heme transport in S. aureus. Moreover, the heme permease IsdF was shown to be associated with FMMs, to interact directly with FloA and to co-localize with the latter in the bacterial envelope. Accordingly, Hb-dependent proliferation was reliant on the correct formation of FMMs. Finally, we demonstrated that appropriate FMM formation is also required for Isd-dependent proliferation of S. lugdunensis, suggesting that FMM-dependent structuring of the membrane is crucial for the functionality of Isd systems in staphylococci.

ABC transporters are classical molecular machines that transport nutrients across biological membranes and allow their accumulation against concentration gradients at the cost of ATP (Rees et al., 2009). Prokaryotic ABC-type importers consist of three functionally distinct subunits, an extracellular substrate-binding protein (SBP), a membrane-located permease and a cytosolic ATPase. In Gram-negative bacteria, SBPs are located in the periplasmic space while the SBPs of Gram-positive bacteria are lipoproteins that are coupled to the extracellular leaflet of the membrane. SBPs bind the target substrate and deliver it to the membrane. The membrane permeases consist of two subunits (homo- or heterodimers) and promote translocation of the substrate. The ATP-binding protein binds to the permease and energizes transport of the substrate by hydrolysis of ATP (Dassa and Bouige, 2001; Locher, 2009; Zolnerciks et al., 2011). It is known that a single ATPase can energize several permeases with different substrates (Quentin et al., 1999) including the iron compound permeases of S. aureus. S. aureus possesses genes for biosynthesis of the siderophores SA and SB (Beasley et al., 2009; Cheung et al., 2009; Cotton et al., 2009). However, the loci encoding their respective importers do not express an ATPase. It has been shown that FhuC, the ATPase encoded within the hydroxamate siderophore transport system fhuCBG, is needed for staphyloferrin-dependent proliferation (Beasley et al., 2009; Sebulsky et al., 2000; Speziali et al., 2006). The isd operon of S. aureus also lacks a gene encoding an ATPase. Here, we show that deletion of fhuC has a major impact on Hb-dependent growth. This suggests that FhuC is a housekeeping ATPase that powers acquisition of different iron compounds by S. aureus. However, weak Hb-dependent growth was observed with the ΔfhuC mutant. This could indicate that an unknown ATPase partially substitutes for the function of FhuC. Such an exchangeability of ATPases was previously described (Hekstra and Tommassen, 1993; Leisico et al., 2020; Webb et al., 2008). Seven ABC iron compound transporters were previously identified in the genome of S. aureus (Sst, Fhu, Sir, Hts, Isd systems, SAUSA300_1514–1517 and SAUSA300_0598–99) with SstC and SAUSA300_1516 being ATPases besides FhuC (Skaar et al., 2004). It seems possible that these are able to partly substitute for FhuC. However, further experiments are needed to validate this. Alternatively, a secondary heme transporter might exist in S. aureus. It is worth considering that Isd-dependent heme acquisition in other pathogens appears to be energized by specialized ATPases. This has been experimentally proven for S. lugdunensis where the ATPase IsdL (Heilbronner et al., 2011) energizes heme transport by IsdEF (Flannagan et al., 2022). Similarly, the isd loci of B. anthracis (Skaar et al., 2006), B. cereus (Abi-Khalil et al., 2015), and L. monocytogenes (Jin et al., 2006; Klebba et al., 2012) possess genes encoding putative ATPases. However, the relevance of these ATPases for heme acquisition lacks experimental validation. Nevertheless, it seems plausible that they are required to energize heme membrane transport in these organisms.

All available knowledge indicates that FhuC functions as a housekeeping ATPase that energizes at least four different iron compound transporters (FhuCBGD₁D₂, SirABC, HtsABC, and IsdEF). Similar cases of ATPases energizing a variety of importers have been reported for other species such as Streptococcus pneumoniae (Linke et al., 2013; Marion et al., 2011), Streptococcus suis (Tan et al., 2015), Streptomyces reticuli (Schlösser, 2000), Streptomyces lividans (Hurtubise et al., 1995), and Bacillus subtilis (Ferreira et al., 2017; Ferreira and Sá-Nogueira, 2010; Morabbi Heravi et al., 2019; Schönert et al., 2006). All these systems are carbohydrate type I importers while those energized by FhuC are type II importers. Type I importers typically have permeases with only six transmembrane domains (TMDs) and acquire substrates like ions, amino acids, and sugars. In contrast, type II importer permeases consist of 10 TMDs and take up bigger substrates like heme or cobalamin (Locher, 2009). However, precise structural motifs that allow interactions between an ATPase and multiple different permeases remain widely elusive. ATPases and permeases interact using Q-loops and coupling helices, respectively (Hollenstein et al., 2007; Locher, 2009). Coupling helices often contain an EAA motif to facilitate interaction with an ATPase (ter Beek et al., 2014). A classical EAA motif is not apparent within the coupling helices of FhuB, FhuG, HtsB, HtsC, SirB, SirC, and IsdF. However, we identified conserved alanine and glycine residues that in combination are necessary for interaction with FhuC, which suggests that these residues are of crucial importance for targeting FhuC. Besides conserved amino acids, the secondary structures of coupling helices are important for the recruitment of ATPases (Beis, 2015; Hollenstein et al., 2007; Locher, 2009). However, the full-length coupling helix of IsdF, when inserted into MntB, did not allow MntB to interact with FhuC. This suggests that additional molecular signatures enable FhuC to identify appropriate interaction partners. Interestingly, deletion of the C-terminal part of IsdF including the fourth cytosolic loop prevented interaction with FhuC. It is possible that truncation of the C-terminal part of IsdF prevents appropriate folding or homodimerization, which might inhibit appropriate interaction with the ATPase. Nevertheless, it is also possible that in addition to a matching coupling helix, interaction between C-terminal residues of IsdF and FhuC is needed to stabilize binding. Further experiments to investigate the molecular structure of the protein complexes by X-ray crystallography are needed to validate this hypothesis.

Interestingly, components of all FhuC-energized transporters are associated with the DRM fraction of S. aureus membranes, suggesting that they are integrated in FMMs. FMMs were previously shown to be important for the oligomerization of cell wall biosynthetic enzymes like PBP2a (García-Fernández et al., 2017), for the function of membrane-bound protein complexes like the type VII secretion system (Mielich-Süss et al., 2017) and the RNase Rny, which is part of the degradosome (Koch et al., 2017) in S. aureus. A role for FMMs in nutrient acquisition has not been described previously. Many different ABC transporters are present in the proteomic profile of FMM-membrane fractions, for example components of magnesium (MgtE), manganese (MntH), molybdenum (ModA), phosphate (PitA), oligopeptide (OppB, OppC), and fructose (FruA) transporters (García-Fernández et al., 2017). It is unclear if this is the result of biochemical characteristics that are shared between membrane proteins or if this association is promoted by the FMM scaffolding protein FloA and is important for import of nutrients. Here, we showed that FloA directly interacts with the permease IsdF, supporting the idea of active integration of permeases into FMMs. If this holds true for other permeases remains to be investigated. However, in the light of shared ATPases it is tempting to speculate that active integration into FMMs can create spatial proximity between permeases and improve the recruitment of energizing proteins such as FhuC to optimize functionality. It is possible that FloA facilitates oligomerization of larger complexes consisting of multiple permeases that are collectively energized. However, we found that disruption of FMMs by mutation of floA interfered with Isd-dependent proliferation but not siderophore-dependent growth. Similarly, we found that the function of sortase is not impaired in a floA-deficient mutant. This indicates that active integration into FMMs is not occurring for all proteins identified by DRM/DSM analysis in membrane extracts. But it is clearly occurring and functionally relevant for some of them.

Previously, treatment with ZA was shown to reduce S. aureus virulence in vitro and in vivo (García-Fernández et al., 2017; Koch et al., 2017; Mielich-Süss et al., 2017). Our data suggest that besides reducing the functionality of virulence factors, limiting the ability to overcome restriction of iron acquisition might also contribute to this phenomenon. Accordingly, statins like ZA might represent a new treatment approach to treat S. aureus infections by targeting diverse cellular functions simultaneously and could lead to the resurrection on β-lactam antibiotics to treat MRSA infections (Foster, 2019; Somani et al., 2016).

Speculation

It is unclear why activity of Isd depends on FMMs while siderophore transport does not. However, there must be a functional difference between the systems explaining this. Only Isd-dependent heme acquisition depends on the activity of CWAs. Interestingly, the Isd-dependent heme transport across the cell wall is structured. Hb binding and heme extraction is facilitated by the surface-exposed receptors IsdB and IsdH. Heme is then passed to IsdA and from there to IsdC. In contrast to the other cell wall-anchored molecules, IsdC is anchored by SrtB, allowing placement of the protein in the central layers of the peptidoglycan (Mazmanian et al., 2003; Mazmanian et al., 2002). This structure is referred to as a ‘heme funnel’ (Sheldon and Heinrichs, 2015) and is thought to allow concerted passage of heme over the envelope. It seems possible that the funnel needs the heme-specific transporter IsdEF to be appropriately aligned with IsdC to allow efficient passage of heme to the membrane (Figure 9). Along this line, FMMs might allow alignment of IsdC and IsdEF. However, a deeper understanding of the spatial location and distribution of IsdC as well as of FMMs is needed to verify this.

Figure 9

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Figure 9—source data 1

Proposed model of heme funneling over the S. aureus cell envelope.

https://cdn.elifesciences.org/articles/85304/elife-85304-fig9-data1-v2.zip

Download elife-85304-fig9-data1-v2.zip

Alternatively, it seems possible that FloA is crucial for formation of the IsdF homodimer within the membrane. It was previously shown that FloA deficiency reduces the formation of protein complexes in the membrane of S. aureus (García-Fernández et al., 2017; Koch et al., 2017; Mielich-Süss et al., 2017). Our microscopy analysis showed that IsdF-derived signals were almost indetectable within a floA-deficient background, which might result from an incomplete folding or homodimer formation which might entail degradation of the protein.

All datasets underlying the diagrams are provided as Source Data.

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Author details

1. Lea Antje Adolf

   1. Department of Infection Biology, Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, Tübingen, Germany
   2. Cluster of Excellence EXC 2124 Controlling Microbes to Fight Infections, Tübingen, Germany
   3. Interfaculty Institute of Microbiology and Infection Medicine, Institute for Medical Microbiology and Hygiene, UKT Tübingen, Tübingen, Germany

   Contribution

   Data curation, Investigation, Visualization, Methodology, Writing – original draft

   Competing interests

   No competing interests declared

2. Angelika Müller-Jochim

   1. Department of Infection Biology, Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, Tübingen, Germany
   2. Cluster of Excellence EXC 2124 Controlling Microbes to Fight Infections, Tübingen, Germany
   3. Interfaculty Institute of Microbiology and Infection Medicine, Institute for Medical Microbiology and Hygiene, UKT Tübingen, Tübingen, Germany

   Contribution

   Supervision, Investigation, Methodology

   Competing interests

   No competing interests declared

3. Lara Kricks

   1. National Centre for Biotechnology, Spanish National Research Council (CNB-CSIC), Madrid, Spain
   2. Research Centre for Infectious Diseases (ZINF), University of Würzburg, Würzburg, Germany
   3. Institute for Molecular Infection Biology (IMIB), University of Würzburg, Würzburg, Germany

   Contribution

   Supervision, Investigation, Methodology

   Competing interests

   No competing interests declared

4. Jan-Samuel Puls

   Institute for Pharmaceutical Microbiology, University Hospital Bonn, University of Bonn, Bonn, Germany

   Contribution

   Investigation, Visualization, Methodology

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-8130-7375

5. Daniel Lopez

   1. National Centre for Biotechnology, Spanish National Research Council (CNB-CSIC), Madrid, Spain
   2. Research Centre for Infectious Diseases (ZINF), University of Würzburg, Würzburg, Germany
   3. Institute for Molecular Infection Biology (IMIB), University of Würzburg, Würzburg, Germany

   Contribution

   Supervision, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-8627-3813

6. Fabian Grein

   1. Institute for Pharmaceutical Microbiology, University Hospital Bonn, University of Bonn, Bonn, Germany
   2. German Center for Infection Research (DZIF), partner site Bonn-Cologne, Bonn, Germany

   Contribution

   Supervision, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

7. Simon Heilbronner

   1. Department of Infection Biology, Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, Tübingen, Germany
   2. Cluster of Excellence EXC 2124 Controlling Microbes to Fight Infections, Tübingen, Germany
   3. Interfaculty Institute of Microbiology and Infection Medicine, Institute for Medical Microbiology and Hygiene, UKT Tübingen, Tübingen, Germany
   4. German Center for Infection Research (DZIF), Tübingen, Germany
   5. Faculty of Biology: Microbiology, Ludwig-Maximilians-Universität München, München, Germany

   Contribution

   Conceptualization, Resources, Formal analysis, Supervision, Funding acquisition, Investigation, Visualization, Methodology, Project administration, Writing – review and editing

   For correspondence

   simon.heilbronner@bio.lmu.de

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-6774-2311

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