As antibiotic resistance increases the search for new anti-bacterial treatments becomes more and more important. One way to design anti-bacterials is to find specific biochemical pathways that the bacteria require to survive, and develop drugs that block off these pathways. Some pathways are better targets than others and for Salmonella bacteria it was thought that pathways dealing with nutrient metabolises would be a lost cause. Salmonella lives in the intestine, which hosts a whole variety of different nutrients, so surely preventing the bacteria from using a specific one wouldn’t cause them much undue distress.
It’s been found, however, that as they grow and spread in the inflamed intestine the bacteria are heavily reliant on one particular nutrient: fructose-asparagine.
The importance of fructose-asparagine metabolism was originally discovered during experiments designed to identify interactions between the pathogenic Salmonella and the normal bacterial flora in the gut. Salmonella mutants, without the genes required to metabolise fructose-asparagine, were introduced into normal mice (with all their gut flora) and into mice who had been treated with antibiotics to remove their gut bacteria. When compared to the wild type salmonella it was found that there was no difference in the normal mice whose gut bacteria were preventing the Salmonella from causing inflammation and disease. However in the antibiotic treated mice, the mutant Salmonella were struggling to cause any inflammation at all.
What these results suggest is that Salmonella might be happy to survive on a range of nutrients while it’s just hanging around in the intestine, but as soon as it becomes pathogenic and starts causing inflammation it preferentially metabolises fructose-asparagine.
The image above shows a proposed model of how the fructose-asparagine is used by the Salmonella, based on the properties of the identified genes. The fructose-asparagine diffuses through the bacterium outer membrane and looses a small section of the molecule (the -NH2 group) in the inter-membrane space. It is then transported through the inner membrane and into the cell where the rest of the metabolises occurs, breaking the fructose-asparagine into glucose-6-P (a simple sugar that can be used for energy) and aspartate.
As well as being seemingly vital for bacterial survival during the inflammatory disease, this also represents a novel pathway not found in any other organism. This makes the fructose-asparagine pathway a perfect target for anti-bacterial therapies as molecules that target this pathway will not harm the human host. The high specificity of such a molecule would also reduce damage to the normal bacterial flora within the gut, and specifically target Salmonella causing an inflammatory illness.
Reference: Ali MM, Newsom DL, González JF, Sabag-Daigle A, Stahl C, et al. (2014) Fructose-Asparagine Is a Primary Nutrient during Growth of Salmonella in the Inflamed Intestine. PLoS Pathog 10(6): e1004209. doi:10.1371/journal.ppat.1004209