Turned up to eleven: Fair and Balanced

Wednesday, July 31, 2002

Future directions in the fight against a global hegemon

Of course, the hegemon I refer to is none other than the "urkingdom" eubacteria, who, especially when paired with the other unicellular branch of the tree of life, the archaea, completely dominate the world's ecosystems, by any measure you wish to use. As lowly humans struggling against the mighty unicellular menace, I want to return to the topic of antibiotic discovery, and the "arms race" between human ingenuity, and billions of years of rapid evolution (rapid, in the sense that bacteria have short generation times, and therefore can change genetically much quicker than larger, slower to reproduce organisms; there are ambiguities here, but we will leave them for another post). I can think of two promising methods, both of which rely on the young but promising field of microbial genomics. Bacteria, being much smaller and "simpler" than us (also, another post), have been most tractable subjects for the hard work of DNA Sequencing. The sequencing project for bacteria has now become so small of an effort that it barely rates a publication anymore, whereas the first sequenced organism, Haemophilus influenzae, rated a publication in Science (1995). In any event, having the sequences of lots of microbes, as well as the draft human genome (as well as several other mammals), can help identify targets in the microbial genome that are more subtle than the ones that are currently attacked (DNA replication machinery, transcription and translation, cell wall synthesis).

Another approach, and one that I think holds the most promise, is the "if you can't beat 'em, join 'em" approach. To quote from a rather obscure source something I am sure I heard more prominently said, "A bacterium's goal is not to become human, but to become two bacteria". Similarly, a pathogen's goal is not to make you sick, but to become two pathogens. One way to approach stopping infectious diseases, at least in some cases, would be to prevent the virulence factors, that is, the things the bacterium makes to make you sick, from being produced. Alternatively, you can specifically target drugs to the virulence factors, or the other factors that regulate them. Let me give an example.

A major organism that causes diseases in people with chronic respiratory disease in particular, but any compromise to their immune system as well, is Pseudomonas aeruginosa. Pseudomonas is what is called an opportunistic pathogen, because it doesn't make healthy people sick, but people with lung diseases (Cystic Fibrosis is the prime example) or immune compromise are susceptible. Pseudomonas has a very interesting life history, for two reasons. One is that it forms a biofilm, where a consortium of cells, not always all of the same species, can form attached very strongly to a surface. Cells in this environment are known to be less susceptible to antibiotics, and can be a real problem. Recent research has suggested that not just Pseudomonas, but essentially all bacteria form biofilms, and spend most of their lives in that state, leaving the interested observer to wonder what the hell we have been studying all these years! Nevertheless, researchers are coming to grips with this reality, and starting in earnest to study biofilms. The other interesting thing about Pseudomonas is that it uses an intricate Quorum Sensing signal mechanism to measure the population of surrounding cells, both physically, and temporally (that is, what stage of the life cycle the cells are in). The details are too involved for this discussion, but quorum sensing controls the production of virulence factors, the shift to biofilm formation, and the production of metabolites that serve to kill competing bacteria.

So, while we can certainly fight this and other bacteria by conventional means (antibiotics), it might be possible to subvert the microbe more subtly, by interfering with the way it communicates with its fellow bacteria. The structure of the signal molecules is well known, and studies using chemically related competitors have already been published. Other methods that might be of use include the introduction of genetically modified bacteria that can outcompete the virulent strains for the same niche in the environment, or biocontrol strains, which either produce specific anti-pseudomonas chemicals, or inhibit quorum sensing in some other way (sorry, that last bit is classified; in the highly competitive world of academic science, even a weblog is no place to divulge current research tidbits).