One of the things that I have always liked about the sciences is that you get a behind-the-scenes look at what’s really going on in the world (which is something I emphasized in various entries in The Chemistry Book). If you’re not a biologist or chemist, one of those little-known but crucial things is how much life depends on an element that most creatures have trouble getting. That’s iron, which is absolutely required for many enzymes, including those handling key steps in metabolism and (famously) for oxygen-carrying proteins. But it’s not in short supply because it’s scarce. There’s iron all over the place, in quantities large enough to stain whole mountain ranges and color the dirt red as far as you can see. But it’s locked up as one of some of the most insoluble lumps in all of inorganic chemistry, the iron oxides and hydroxides. In the ocean, iron is often a limiting factor for plankton growth, and you can create a spectacular bloom with a helicopter and a load of soluble iron salts. (This has been suggested as a possible route for carbon sequestration, but as that link will show you, it’s not so simple – the amount of carbon sequestered also depends on the available silicon for diatoms to form).
There are bacteria that make a living off of iron oxidation states (there are bacteria and fungi making a living off of most any source of chemical energy you can imagine), but they all have to deal with the huge insolubility of the higher oxidation state Fe(III) compounds. In recent years, iron oxide nanoparticles have become an area of study, and it looks like these are (for better or worse) more bioavailable for bacteria than the usual iron oxide forms when released into the environment. A lot of bacteria (the ones that aren’t working the iron oxidations states in particular) are quite keen on sequestering whatever iron they can get, thus you have a whole class of natural products (the siderophores) that coordinate the metal to an almost unbelievable extent.
This is an issue in human bacterial infections, because our own bodies are not wasting much iron, either. The free concentration of iron in human tissue (outside of what’s bound up in hemoglobin, iron-based enzymes and the like) is estimated to be about ten to the minus twenty-fourth molar, so there’s not much to go around. And even at that, one of the responses to a bacterial infection (nutritional immunity) is to pull back sources of iron even more. Here’s a recent overview of the field, which presents some interesting ideas for antibacterials. Bacteria are especially good at taking up heme species, since those are the most abundant iron compounds in higher organisms, and blocking these pathways definitely puts a strain on them. Another set of targets involves interfering with the biosynthesis of the siderophore compounds themselves. Yet another possibility is to give a patient iron-coordinating compounds that will compete for whatever iron is around and make it less available for the bacteria, but that’s one that you’d want to be careful with, since we need the stuff, too.
And there’s another iron-centric strategy that’s being tried – conjugating known antibiotics to known siderophores, in the hopes that bacterial will take in this Trojan horse in their constant search for iron. (Interestingly, bacteria are not above “siderophore piracy”, leaching off the hard work of neighboring bacteria by vacuuming up the iron complexes others have produced – actually, bacteria are not above any survival strategy whatsoever, which is one of the things that makes fighting them so difficult).
These kinds of ideas have gotten more traction in recent years, because the traditional routes to antibacterials have not been as productive as we need them to be. I’m glad to see it, having worked in antibacterials myself for a bit, because we’re going to need all the help we can get, and it’s been a long time since the fluoroquinolones (not to mention the beta-lactams or the tetracyclines). Antibacterials would seem to be the prime example of an area in which the low-hanging fruit has been definitively stripped off the trees, and we need ladders, cherry-picker trucks, and whatever else can be brought in to find more. Good luck to the iron-targeting people – we’re all going to need it.