For this post I am going to talk again about drug discovery but in a manner that is really an emerging area of research. The lab I’m working in, though not I personally, have been collaborating with another group at Rockefeller University to study the genomes of the bacteria Rhodococcus equi and R. erythropolis (1). These are bacteria which normally exist in our oral cavities, our nose, and our mouth, but sometimes end up growing in our gut. We’ve talked in a previous post about how changes in your gut microbiome can affect your health. Here, in this paper, we asked the question: what are different types of bacteria doing in your gut and could they actually be useful to us?
Gut bacteria produce all kinds of different molecules that act as signals to your body and towards other bacteria. Your gut is almost like a Wild West of bacteria as well as fungi and viruses, all of which are fighting to survive. When you have the right balance of these organisms you exist in a stable state or “homeostasis”. How do some organisms end up tipping the balance and getting a foothold in the gut? The answer likely comes from the molecules that they produce! Certain types of bacteria might have a way of inhibiting the growth of other bacteria which allows them to overpopulate your gut. We would want to study these bacteria in particular to see what they are doing to our normal homeostasis.
Many of these bacteria are finely tuned to survive in the environment that our bodies provide to them. How can we understand what they are making if we can’t grow enough of them outside of our body? This is where genetics comes in to the picture. We’ve mentioned before one of the central dogmas of biology, that the DNA in a genome encodes for specific protein sequences. Dr. Brady’s lab at Rockefeller looked at the DNA sequences in several portions of the Rhodococcus equi and R. erythropolis genome where we might anticipate active peptides to be encoded. His lab then manually synthesized the peptides that those sequences encoded using synthetic chemistry and tested them against various bacteria and in combination with other drugs called beta lactams (this is the class of drugs that includes Penicillin). They found two active drugs which they called, Humimycins. When they studied these drugs in bacterial culture and when we studied them in mice we discovered that they seem to target a protein complex called a “Flippase”. These Flippases, as the name suggests, have the ability to flip drugs like penicillin to the outside of the cell, thus rendering them ineffective. If you are a bacteria that can inhibit Flippases you can confuse your neighbors and cause dysregulation and you can inhibit their growth.
While this all sounds very exciting there are a few questions that we need to ask about these Humimycins. The first question is: if these drugs are active against specific types of gut bacteria, what effect would using them have on our normal gut microbiome? You might eliminate MRSA for instance but would some other type of bacteria take over your gut? Again this begs the question of what exactly is the “normal” situation in your gut? This is a difficult question and it’s still an area of research that requires an enormous amount of research. For now, because of how difficult beta-lactam resistant bacteria are to deal with, we might as well explore every option we have in our antibiotic arsenal. Overall I think the most encouraging sign is that we are now considering how antibiotics and other drugs affect the microbiome and we are utilizing genetics to try to gain a better understanding of it.
Thanks for reading! I’ve got a few of my own papers in the works so hopefully I’ll be able to discuss it more soon! Cheers!
1 Chu J et al. Discovery of MRSA active antibiotics using primary sequence from the human microbiome. Nature Chem Bio. 2016. doi:10.1038/nchembio.2207