My department had a visiting speaker this week, Dr. Sean Moore from the University of Central Florida. It was a really interesting talk, and Dr. Moore had a unique perspective on the way we use antibiotics against bacteria.
As microbiologists, we spend a lot of time and energy trying to understand the mechanisms bacteria use to invade human cells and cause disease. The idea being that if we understand how and why it happens, we can interfere with the process or prevent it from happening. Bacteria have been around much, much longer than humans, though. They didn't develop these mechanisms in the hopes that a human-like host would come along so that they could use them to invade human cells. The bacteria are just trying to survive inside an especially hostile environment, using whatever molecular tools they happen to have. Most disease-causing bacteria in humans only cause disease when they recognize that they are in a hostile environment. If they are colonizing an animal host or living in dirt or water they are not producing the chemicals or activating the pathways that make humans sick. They are happier and healthier that way, too. Virulence takes energy away from things like obtaining nutrients and cell division.
It's easy to lose sight of the fact that bacteria are not sentient. We anthropomorphise them all the time, even in science. We say that they are attacking or killing us, but they aren't. They're just surviving. Most of the symptoms we experience while sick are actually caused by our immune system as it tries to destroy the invaders. In fact, we are host to about 100 bacteria for every human cell in our body. They live on our skin and in our intestines, and without them we would be screwed. If you've ever had intestinal problems or persistent sickness after being treated with a broad-spectrum antibiotic, that's why. You basically wiped out most of the bacteria living in you, creating a vacuum that was filled up pretty quickly with whatever new bacteria you happened to encounter...only these new bacteria weren't adjusted to the unique environment that was you, and your immune system wasn't familiar with them. Sure, sometimes these gut bacteria can go virulent and cause problems, but that usually only happens when something else is wrong already.
Dr. Moore asked what if, instead of using antibiotics to kill bacteria, we instead communicated with the invading cells and convinced them that there was no reason for them to be virulent? Bacteria interpret signals from their environment to determine which pathways to activate, when its safe to divide...their overall behavior in general, really. If some signaling pathway could be used to convince the bacteria that they are still growing in say, dirt instead of your intestine, then we may be able to save ourselves a good bit of trouble. Antibiotics are undeniably effective and absolutely should be used to treat infections, but bacteria are becoming resistant to them faster than we can make new ones. Eventually, it wont be a very viable strategy anymore.
The trick to developing antibiotics is specificity. Prokaryotes are very similar to eukaryotes in many ways, so identifying compounds that will kill bacterial cells without killing human cells is challenging. You have to identify things that are distinctly unique about bacteria, and disrupt them as much as possible. Penicillin for example works by blocking peptidoglycan cross-linking. Bacteria can't form cell walls, and they die. Eukaryotes don't make peptidoglycan, so it doesn't affect non-prokaryotic cells at all. It works pretty well, until the bacteria learn how to make B-lactamases that chew up the penicillin. Then we introduce B-lactamase inhibitors, and the arms race continues. Drug companies screen thousands of small molecules, trying to identify ones with antibiotic activity. The rest of them are dismissed. Signaling compounds for mediating virulence rather than killing bacteria could very well be among them, but we have no way to screen for that kind of effect...especially since we really have no idea what we would be looking for.
The science is interesting, but still extremely preliminary. It's basically an idea and some computer simulations at this point. What really boggled my mind was the difference in philosophy. Our response to bacteria is often very emotional. We want to destroy the little buggers. We want revenge because they made us sick, but that isn't a logical response. Wars end because people agree to stop fighting. What Dr. Moore is suggesting is a significant paradigm shift, which I think could open up a lot of new possibilities and avenues of research.
So the speaker was suggesting a symbiotic relationship with the invading bacteria? What was suggested to portray the intent to the bacteria that it was living in dirt? Was there any mention of using similar means to counteract viruses? Some way of making them think there was no receptors that let the virus in to a cell?
ReplyDeleteThe speaker was really just suggesting changing the way we think about dealing with bacteria. There's so little actual data available at this point, we have no idea how a new approach might manifest. We may identify a particular molecule found in dirt that the bacteria looks for to identify that environment. It's all speculation, though. I think it's more likely that we would prevent the bacteria from activating virulence genes until our immune system could clear them out. I wouldn't expect symbiosis. Viruses don't really work the same way that bacteria do. They don't really communicate with their environment, they just kind of exist until they find something their surface receptors can interact with. You can't really make them think those receptors don't exist, but you can block the receptors with small molecules. That's how a lot of specific anti-virals work.
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