by Julian Davies
This is in response to Mark Martin’s prompt*; he is an interesting and eclectic character. Well, I was not inclined to write anything, but since this week has been spent on grant writing (for not very much money, this being the style in Canada) and today, being a sunny day, I decided to cut the grass but the handle kept on coming detached from the push mower which put me in a good mood for a rant (not a blog); I am also upset about the fact that Roger Federer lost again and I don't like to see bad things happen to my heroes. But to come back to Mark's prompt, why do microbes make so many small molecules?
To start with I apologize for the fact that the question is biologically incorrect, since the only people who can answer "why" questions are priests. However, you know what I mean. I am very enthusiastic about the fact that the scientific world is becoming interested in biomes and their importance to eukaryotic life; it is about time! Jeff Gordon, Jeremy Nicholson, and others have confirmed the notion that bacteria are really good for us humans and we can begin to think seriously about microbes as being truly important living beings. As you know, I have long been interested in how microbial small molecules fit into this picture.
As I pointed out in an earlier letter, there is a humungous microbial world of small molecules of great structural diversity (Mark Martin suggested "parvome," from the Latin, parvus, for "small," and I agree; I have always wanted my own "-ome.") Microbes are the most accomplished chemists on earth; interestingly, one of the greatest challenges for organic chemists is to design synthetic approaches to these molecules and many naturally-occurring compounds remain to be so made. But these small molecules were not produced to be PhD projects and neither were they made to cure our infectious diseases. The latter is one of the best examples of anthropocentric thinking, in my opinion. We use bacterial small molecules as drugs precisely because they exhibit dose response curves. At high doses they are good for us but at low doses they must possess activities that are good for microbes, more especially for microbial communities (the only way that microbes exist in nature – well, maybe not in invasive infections).
So what do small molecules do? Our studies show that all natural products are bioactive, in the sense that at low (sub-inhibitory) concentrations they modulate bacterial transcription. Depending on the compound and its target, each small molecule influences a distinct spectrum of promoter responses. To me and some others, this implies that in the environment, bacterial communities are modulating their activities using a wide range of small molecule signals.
I could say that this was a form of homeostasis, but it is premature to make this conclusion. I could also say that bacteria all have their own cell phones but this is a primitive anthropomorphism! I think we must accept that this is a different form of cell-cell signaling than is normally discussed, since the small molecule ligands interact with macromolecular receptors such as ribosomes, or the DNA replication, transcription, and cell wall complexes. All this remains to be proven, of course, and some good imaging studies in soils and other environments would help.
On the other hand, some small molecules are so toxic that it is difficult to see how they could be anything other than real antibiotics. A good example is the enediyne class produced by a number of different bacteria and used as antitumor agents. Bacteria make them, use them (for what purpose?), and survive! The self-protection mechanisms must be extremely effective since one slip means death. Incidentally, I wonder if the natural bacterial protection mechanisms could be used to control the activities of these potent compounds during cancer chemotherapy? Someone must have thought of this.
Finally, there has been much discussion of late about the "environmental resistome." One can certainly find endogenous antibiotic resistance genes in most bacterial populations by cloning and testing in the lab. But is this their real function in nature? Could resistance be due to pleiotropic effects? Is much of the clinically significant resistance simply due to the over-expression of a heterologous gene in a different cytoplasm?
So there you are. I hope that you have no concerns about my sanity; you can blame this post on Mark!
Yours in wonder (about microbes).
*Mark’s prompt: I would love to see a post from Julian Davies from UBC over his idea (presented at ASM) that there exists a microverse of small molecules in nature which have profound effects on microbes in the natural world.