Bacterial siderophores in community and host interactions

Abstract

Iron is an essential trace element for most organisms. A common way for bacteria to acquire this nutrient is through the secretion of siderophores, which are secondary metabolites that scavenge iron from environmental stocks and deliver it to cells via specific receptors. While there has been tremendous interest in understanding the molecular basis of siderophore synthesis, uptake and regulation, questions about the ecological and evolutionary consequences of siderophore secretion have only recently received increasing attention. In this Review, we outline how eco-evolutionary questions can complement the mechanistic perspective and help to obtain a more integrated view of siderophores. In particular, we explain how secreted diffusible siderophores can affect other community members, leading to cooperative, exploitative and competitive interactions between individuals. These social interactions in turn can spur co-evolutionary arms races between strains and species, lead to ecological dependencies between them and potentially contribute to the formation of stable communities. In brief, this Review shows that siderophores are much more than just iron carriers: they are important mediators of interactions between members of microbial assemblies and the eukaryotic hosts they inhabit.

Figure 1. Representative examples of the four main chemical classes of siderophores.

Siderophore is a functional term and includes a chemically diverse group of molecules. The four main types are distinguished based on the moieties involved in iron chelation, which entail catecholate, phenolate, hydroxamate and carboxylate functional groups (grey shadings). Siderophores with mixtures of functional groups are also common. Representative siderophore examples include enterobactin (which is produced by Escherichia coli, for example), pyochelin (which is produced by Pseudomonas aeruginosa, for example) featuring a heterocycle (thiazoline) ring, alcaligin (which is produced by Bordetella pertussis, for example) and rhizoferrin (which is produced by Ralstonia pickettii, for example). Note that the same siderophore can be produced by different species.

Figure 2. Comparing siderophore-dependent and surface-dependent iron-uptake systems.

Considerations of why bacteria have evolved siderophore-mediated iron scavenging systems (green cells), where siderophores can be lost due to diffusion, as opposed to surface-dependent iron uptake mechanisms (purple cells), where benefits are secured. We consider cases in which iron is either relatively homogenously distributed (as small particles along a blue-shaded gradient) or occurs clumped in large particles (blue circles). Siderophores increase the range across which iron can potentially be sequestered (yellow area) and the amount of iron that is brought into solution (orange-red gradient), but are at the risk of not finding their way back to producers (arrows). The siderophore’s reach of action (yellow area) depends on the viscosity of the environment and the chemical diffusion property of the siderophore. Emojis inside cells depict the relative fitness consequences of the two iron-scavenging strategies. a | When iron is homogenously distributed and cells are motile, surface-dependent iron uptake mechanisms are efficient for iron scavenging, and siderophores unlikely confer an advantage. b | When iron is homogenously distributed, but cells are attached to surfaces, siderophores can access iron beyond the local pool, potentially making it available for bacterial metabolism. However, many siderophore molecules might get lost due to diffusion. c | When iron is clumped and cells are motile, bacteria with surface-dependent iron uptake mechanisms must necessarily make contact with the iron source to be able to take up this nutrient, whereas no direct cellular contact is required with siderophores and more distant iron pools can be accessed. d | When iron is clumped and cells are non-motile, siderophores might be the only way to obtain iron. These considerations suggest that siderophore production is most beneficial when iron resources are clumped and cells are non-motile.

Figure 3. Siderophores can synergistically increase iron uptake when bacteria live in groups.

The problem of siderophore loss due to diffusion can be reduced when cells live in groups. In this scenario neither the diffusion range of siderophores (yellow) nor the amount of iron brought into solution (orange-red gradient) increases per cell, but the probability of iron-loaded siderophores returning to cells increases, because cells can access each other’s siderophores (brown area, double black arrows). Emojis inside cells depict the relative fitness consequences for a cell in the different scenarios. This synergistic effect manifests irrespective of whether the iron is relatively homogenously distributed (a, b, blue-shaded gradient) or occurs in clumped particles (c, d, blue circles) in the environment, or whether cells are motile (a, c) or surface-attached (b, d).

Figure 4. Siderophore-mediated social interactions.

The figure shows representative examples of social interactions driven by secreted siderophores (partial circles) that bind insoluble iron (blue squares) and for which specific receptors (cylinders) are required for uptake. Emojis inside cells depict the relative fitness consequences for the interacting partners. a | During cooperation in clonal groups, siderophores are mutually shared and accelerate iron uptake through a common siderophore pool. b | Cheating happens when siderophore non-producers have the matching receptor for uptake and thereby exploit the common pool of siderophores without contributing to it. c | Competition can happen when producers lock iron away from non-producers that lack the matching receptor for heterologous siderophore uptake. d | Another competition scenario involves two species that each produce their specific siderophore. The competitive strength of the species is influenced by the amount and kinetics of siderophore production and the iron affinity of their siderophores.

Figure 5. Siderophores induce eco-evolutionary dynamics in bacterial communities.

a | If siderophores (yellow partial circles) are essential for growth, siderophore producers (green cells) and non-producing cheaters (red cells) can co-exist in a community through negative frequency-dependent selection. b | Strains or species with different siderophore strategies can engage in non-transitive community dynamics, and thereby co-exist and foster biodiversity. The example depicts interactions between a cheater (red) outcompeting the siderophore producer, which secretes a compatible siderophore (green). This siderophore producer in turn outcompetes the second siderophore producer (blue), secreting a less potent siderophore. This weaker siderophore producer, however, outcompetes the non-producer because it produces a siderophore for which the non-producer lacks the matching receptor. This scenario leads to a rock-paper-scissors dynamic, in which strains chase each other in circles with no overall winner. c | When, in addition to siderophores (green partial circles), a second public good is important for growth (yellow flash, for example, proteases required for extra-cellular protein degradation), specialization could evolve, leading to each strain or species producing only one public good and exchange at the community level. Emojis inside cells depict the relative fitness consequences for the interacting partners.

Figure 6. Siderophores and their effects on hosts.

a | Siderophores (yellow shaded zones) from beneficial rhizosphere bacteria (green cells) can protect plants from pathogens (blue cells) and their virulence factors (blue shaded zones), and keep the plants healthy (left green plant). In this scenario, siderophore incompatibility between the plant beneficial bacteria and the pathogen is thought to lead to plant protection. b | Siderophores (yellow shaded zones) of pathogenic bacteria (green cells) can function as virulence factors and damage host tissue and promote pathogen growth (left lung). If siderophore non-producers (red cells) occur or de novo evolve in such infections, they can act as cheaters. If these cheaters can spread the induced cooperator-cheater dynamic can potentially lower the virulence of the infection. Emojis inside cells depict the relative fitness consequences for the interacting partners.