The secretion of small molecules is likely one of the most common ways in which bacteria interact with other bacteria, regardless of their environmental setting. Like many others, I like to refer to that universe of chemical interactions as "bacterial chemical ecology." Now, for a moment, try to visualize how you might ideally study these interactions. If you are like me, you'd want to have some set-up whose scale is relevant to the size of the bacteria in question. For example, look at antibiotic production within sub-millimeter spaces. I'd also want the bacteria to be in their natural setting or somewhere about as close as possible to that. Yet, when I think about how I normally used to determine the effects of antibiotic production by one strain on another, I grew them to enormous populations sizes (colonies on plates) and under conditions that they would never encounter in natural settings. Not a very good proxy I would say. Somewhere in the back of my mind, I always harbored the idea of finding miniscule ecosystems to study the possible ecological roles of antimicrobials. That is why I was so very pleased to read a paper by Jan Claesen and colleagues (a large collaborative effort led by the laboratories of Katherine Lemon and Michael Fischbach) addressing bacterial chemical ecology within a very small ecosystem, namely the hair follicles of human skin.
Knowing that the human microbiome abounds with biosynthetic gene clusters (BCGs) that encode the production of secreted specialized metabolites – some of which are antimicrobials – the authors set out to test the hypothesis that some of these antimicrobials play a role in modulating skin microbial community composition. They homed in on a particular BCG that was prevalent in the genomes of cultivated strains of Cutibacterium acnes, bacteria that are abundant in human skin. The purification and characterization of the product of this BCG revealed it to be a new thiopeptide which they named cutimycin. The thiopeptides are remarkable because while they start out as a short ribosomally synthesized peptide, their backbone and side chains are extensively modified after translation. For fun, have a look at the primary amino acid sequence and then the final product of cutimycin (see Fig. 1). Do you get a sense of what some of these post-translational modifications are?
In addition to determining the structure, the authors also showed that cutimycin is an antibiotic that can inhibit the growth of Staphylococcus aureus and Staphylococcus epidermis but it does not inhibit several Cutibacterium strains. Having all this information, they went on to test the hypothesis that on the skin cutimycin-producing strains have the effect of reducing the numbers of Staphylococci. Here is where I think they were particularly clever in their choice of microecosystem. They chose human skin hair follicles. You might ask, how did they get ahold of human hair follicles? The beauty of their approach is that it is rather straight forward to collect large numbers of these using a readily available tool, adhesive strips that are used cosmetically. By applying these adhesive strips to the nose and then stripping them off, individual hair follicles are easily pulled away (see Frontispiece). Using healthy human volunteers, they collected and analyzed more than 150 individual hair follicles. From each follicle they cultivated C. acnes and S. epidermis. This way they quantitated colony forming units per follicle (CFU/follicle). They then used PCR to determine which of the C. acnes isolates had the cutimycin BGC. Fig. 2 shows the ratio of C. acnes to S. epidermis for each follicle. The bar graph is color coded such that in orange are the follicles where the cutimycin BCG was present and in gray the follicles without that BGC. It is immediately apparent that follicles with high C. acnes-to-S. epidermis ratios are more likely to have the BCG cluster (more orange bars towards the left). On average, follicles with the BCG cluster present had about a ten-fold higher C. acnes-to-S. epidermis ratio. Clearly, the ability to make cutimycin by one member of the community lowers the numbers of another showing an ecological role for this antimicrobial. As most everything in ecology, this is not an all-or-nothing effect. The overall ecology is likely governed by a combination of many factors, cutimycin being just one. Nonetheless, this is an extremely exciting microecosystem to study bacterial chemical ecology. Plus, these findings could have practical applications. In the authors' words: "...we demonstrated cutimycin-mediated competition between C. acnes and Staphylococcus in human skin hair follicles with reduced growth of Staphylococcus. This suggests potential applications for cutimycin, or cutimycin-producing bacterial strains, in preventing or treating diseases associated with a shift in the composition of the skin microbiota."