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Are antibiotics a weapon or a signal?

(Guest blog by my PhD student, Will Ratcliff)

If we get a nasty bacterial infection, we all know to go to the doctor for antibiotics. Few of us stop to think of where these antibiotics come from, which is too bad, because their origin is rooted in the stuff of a James Bond film: bloodsport and espionage. Scientists put a few different microbes on a Petri plate, let them duke it out, and then steal the chemical secrets of the victorious strain. Antibiotics are thus considered by most microbiologists to be pure weaponry, honed by natural selection for the most effective killing (or disabling) of competitors at the lowest cost.

But some recent papers suggest a new hypothesis: antibiotics are actually signaling molecules that happen to be toxic at high doses (Mlot 2009). As evidence for this view, researchers note that microbes exposed to antibiotics at sublethal concentrations don't simply shrug off the insult and go about their business: they react. Some bacteria turn on their SOS response, some make biofilms, some fail to make biofilms, some get less virulent (Shank and Kolter 2009), and yet others more virulent (Linares et al. 2006). These responses appear to vary among species without a general pattern.

So are antibiotics serving as a weapon or a signal?

Let's start at square one: what do they mean by signal? Many of the papers in this literature seem to use signal to mean "molecule produced by species A that elicits a response in species B other than death". But to evolutionary biologists, it matters why species A produces the signal and why species B reacts as it does....

According to Steve Diggle et al. (2007), communication can be divided into three categories depending on the fitness consequences to each party :
Signal.jpg
The defining feature of a signal is that it has evolved because it increases the fitness of both the producer and the receiver. So we arrive at the central evolutionary problem with signaling: when is it beneficial to expend energy to provide another organism (perhaps of another species) with information that will increase its fitness?

A few scenarios I've thought up -- I'm sure there are more -- are A) when this reduces chances that you or your kin will be injured or eaten (e.g. I'm poisonous and if you eat me we'll both regret it) B) when this deters potential competitors from inhabiting the same area as you or your kin (e.g. I'm already halfway done with the food, and am not inclined to share, so you should probably go somewhere else), or C) when it is necessary for the initiation or maintenance of a mutualistic interaction, like the a legume root nodule by rhizobia. For cases A or B, at least, the sender may benefit from sending this message even if it is false, an example of coercion (or at least manipulation) analogous to Viceroy butterflies or back-arching cats that appear larger than they really are.

Before we can state with any confidence that an antibiotic is a signal, we need to know if producing and responding to a sublethal dose of the antibiotic produces benefits for both the producer and the receiver. Benefits like 'not dying from the antibiotic' don't count, nor does 'going into a biofilm preadapts a microbe to unexpected protozoal grazing '. These are questions that will probably be answered as microbial ecology moves forward.

If sublethal doses of antibiotics aren't signals, how do we explain their effect? Biofilm formation by bacteria exposed to antibiotics may increase their antibiotic tolerance, increasing their fitness at the expense of the antibiotic producer. From our previous definitions, the antibiotic would be a cue, not a signal. Similar arguments could be concocted for the production of detoxifying enzymes like β-lactamases or turning on the SOS response. An even simpler hypothesis is that some of the observed responses are not behavioral, but are the observable impact of an injury. Mucking about with a bacterium's ribosomes may not kill it, but it will likely leave some measurable impact.

Finally, antibiotics may simultaneously act as both a weapon and a signal. Assume that the concentration and effectiveness of an antibiotic drops off with distance from a producing microbe. Low concentrations of antibiotic may be an ineffective weapon, but can still effectively signal that any further encroachment on the antibiotic producer's turf is dangerous. Note that avoiding the killing zone of an antibiotic increases the exposed microbe's fitness (it does not die) and that of the producer (competition from other microbes is reduced). Right now this is pure speculation, but I wouldn't be surprised to find out that it's true.

Mixed up in all this is a general misunderstanding of the processes that natural selection optimizes. Linares et al. (2006) stated that:

"We thus could start to envisage a Copernican turn-about for the role of antibiotics in nature: from weapons involved in microbial struggle for life to collective regulators of the homeostasis of microbial communities."
This is essentially an old-school, group-selection argument, positing that individual species have evolved mechanisms to regulate the broader community because communities that are regulated do better. However, since the rate at which communities reproduce and die is slow relative to that of individual microbes, and their species composition is highly fluid, individual selection and kin selection swamp community-level selection. It is very unlikely that individuals would evolve mechanisms for the regulation of the community as a whole.

The bottom line: Simply observing that bacteria respond to sublethal antibiotic exposure does not provide any evidence that antibiotics evolved for the purpose of signaling or have been appropriated as a signaling agent. Indeed, even if antibiotics act only as a weapon, we expect bacteria exposed to sublethal antibiotic concentrations to respond either by being injured, or by acting to minimize injury (antibiotics acting as a cue). While we know that antibiotics can act as a weapon, we don't have any clear evidence that antibiotics act as a signal. Until we have these data, I wouldn't give the signaling hypothesis much weight.


LITERATURE CITED
Diggle S. P., A. Gardner, S. A. West, and A. S. Griffin. 2007. Evolutionary theory of bacterial quorum sensing: when is a signal not a signal? Philosophical Transactions of the Royal Society 362: 1241-1249
Linares J. F., I. Gustafsson, F. Baquero, and J. L. Martinez. 2006. Antibiotics as intermicrobial signaling agents instead of weapons. Proceedings of the National Academy of Sciences 103:19484-19489.
Mlot C. 2009. Antibiotics in nature: beyond biological warfare. Science 324:1637-1639.
Shank E. A., R. Kolter. 2009. New developments in microbial interspecies signaling. Current Opinion in Microbiology 12:205-214.

Comments

It’s a dog’s life?

Just the other day two evolutionary biologists were walking through a neighborhood by campus on their way to a local pub. There in a trash can by the curb they noticed a sign marked: Beware of dog. Next they spotted a woman sitting on the stoop of her house, head in hands. One of our intrepid scientists stopped to talk to the distraught young lady. It turned out her pet had just died and she no longer needed the sign. Our inquisitive biologist asked if he might take the sign. She allowed it.
Our second scientist inquired of the first, “What are you going to do with that sign?”.
“It reminds me of the Journal Club discussion we just left”, said the first.
“How so? I don’t recall talking about dogs.”

Then the following monologue flowed forth:

Well, we were talking about types of communication, right? So this is a sign meant to communicate a message. Its simple and straight forward… or is it? I might take it home some weekend and give it to my Mom. She doesn’t have a dog, but she is concerned about stories there’s a peeping Tom in her neighborhood. This sign might put her at ease.
If she did this, would the sign be a signal, a cue, or a weapon? Do we need more categories? And my Mother, if she did this, would we consider her a cheater?

Alternately I might send this sign to Tony Dungy with the suggestion he put it up on Michael Vick’s new locker in Philadelphia. In the event Tony did this how would we evaluate the sign? What would the message have been years ago if someone had put this sign on Michael’s locker in Atlanta? Same sign, same audience, different historical context.

You know my cousin Larry the creationist? I could photoshop this sign onto the screen in a photo of Richard Dawkins making a presentation. Then I’d caption the photo: “Dyslexic Atheist?”. This one is particularly complicated because Larry might think I’m attacking his personal beliefs, or he might think I’m just trying to brighten his day with some sophomoric humor. Without more context, the communication can be perceived as threat or gift.

Suppose I wrap it up and send it to the White House. Some political wag might look at the sign and decide it has one too many letters. Cross out d-o-g and write Bo in its place. This would send still another message.

Or maybe we could have a good time modifying the sign just a bit and thinking about the new messages it could send. For instance, swap an ‘h’ for the ‘d’ and post it in a farmer’s yard. Or sub an ‘l’ for the ‘d’ and give it to a forest ranger. And Cathy, your herpetology buddy, you could swap a ‘fr’ for the ‘d’ and give it to her. We could replace the ‘d’ with an ‘f’ and give to Doc Freezin over in meteorology. My point in all these spelling options is that a small change (like a mutation) can change the meaning. But you should also take note that these spelling modifications will only work for English speaking audiences. We’re not likely to get the intended responses in Beijing.

From this simple sign we can take away two completely different lessons. First – context is very important. And second, the ability of the audience to infer a message from the sign is also important.

Or second biologist, now duly impressed, stopped and took the sign in his hands to look it over carefully. He shook his head acknowledging the simple insights he’d just been handed. Then he offers, “Why I think you’ve overlooked another lesson we could learn: If you take a ‘Beware of dog’ sign from the trash, you might be a Red Neck”. Then returning the prize he said, “Here’s your sign”.

With apologies to Jeff Foxworthy and Bill Engvall.

Maybe "manipulation" would be more general than "coercion." Falsely claiming to have a guard dog would qualify as manipulation. This claim would only qualify as cheating if there was some group benefit but individual cost to keeping a dog.

Thanks for your response Clem. I completely agree, the interpretation of any signal will depend on the receiver's historical context. In the microbial world, we might say that a single quorum-sensing molecule could act as either a signal or a cue, depending on the recipient. But your example isn't a perfect analogy for antibiotics, because unless you are beating somebody over the head with your "beware of dog" sign, it's got only one purpose: to convey information. Unlike molecules that are unambiguously signals (like the previously mentioned quorum sensing chemicals), antibiotics by definition have the potential for direct physical effects on the recipient. For the reasons I detailed in my blog post, I don't think we've got good evidence yet that antibiotics are made to convey information as well.

Caught your antibiotic summary and really do not agree with your reasoning. Antibiotics do somewhat act as a signal, depending on the virtual outcome of the illness, such as if it works or not-it will help in determining how to retreat someone

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@Will -
Few analogies are perfect, and I agree this one comes up short; but I don't think one needs to go to the length of beating another over the head. I imagine the secreted chemicals in question to be left in the environment and not actually wielded like an axe or spear.

Perhaps the model might look more like a land mine if we need to use human activities to build our analogies. And so I want to go back and defend the "Beware of dog" sign a little bit longer. One typically puts up the sign and walks away. True, the sign itself isn't likely to kill anyone (save perhaps some poor earthworm who happens to be in the way when the stake is driven in the ground - collateral damage). But there is a chance the peeping Tom might trip over the sign at night and break his arm. True enough this is not a result of the sign's intended message, but is still a result of the sign's existence. (another unintended consequence is the newspaper delivery person tripping over it and getting hurt). So unless the antibiotic molecules can be shown to be secreted in response to specific 'enemy' signals and delivered in lethal doses then I have some concerns about the weaponizing interpretation.

As the poison is in the dose - and we know there are significant dose/response relationships with these chemicals - then one might suggest that the lethality of these compounds to some organisms is as much collateral damage as it is intended outcome.

BTW, I think its great that Ford allowed you to post your piece here in the first place. And while I want to quibble with some of your details, I do think its a nice piece.

@Ford:
We have a dog, she is half Rottweiler and half Lab. Folks who've never met her before usually give her a wide berth. Feeding her alone is a significant cost, borne by my wife and I and not by the neighbors.

Our dog is a great pet and I don't want to intimate that somehow my wife and I are altruistic neighborhood champions because we bare the cost of maintaining the beast... but back to our analogy. Using the beware of dog sign without paying to support a dog, well, looks a bit like cheating to me (in an ecological/evolutionary sense).

BTW, Cleo - the dog... she's a lover not a fighter.

I'm not sure "let" is the right word. I liked Will's guest post and it freed me to work on my book.

@Clem:

Unintended side-effects, like the newspaperman tripping over the sign, occur for all biological traits. In the end these vicarious events are manifest as "noise" and don't have a directional effect on the evolution of a trait. For example, one could further the speculative argument with a “but that’s a good thing that the newspaperman tripped over the sign, because by delaying his route by 5 minutes, he was miraculously saved from the drunken driver that would have otherwise killed him”. What I’m concerned about is the evolutionary origin of antibiotics, not their occasional effect.

To prevent overreliance on analogy, lets bring this back to the topic at hand. Similar arguments have been put forward for antibiotics: some induce the formation of biofilms, which are protective against stresses like antibiotics or protozoal grazing, but which have costs like a reduction in growth rates and dispersal. Without noting these costs, some have said that this is evidence of a beneficial role of antibiotics, because of course; we all know that biofilm formation is good. This argument fails for the simple reason that if biofilm formation in the absence of antibiotics were optimal, microbes would have long ago evolved to form them without being “signaled” (to be consistent with my post, I would probably use the term “cued”) to do so by antibiotics.

More importantly, we know that antibiotics play a strong role in preventing invasion from competitors (http://www.springerlink.com/content/nq832v65g2723672/), and that they are likely not accidental killers: antibiotics exhibit many independent, specific mechanisms of action that effectively kill or disable susceptible microbes (http://www.tufts.edu/med/apua/Miscellaneous/mechanisms.html). Antibiotics are different from poisons like mercury that have toxic side effects, because their poisonousness is shaped by natural selection. I find it very unlikely that these lethal consequences are side-effects of some more benign function. If the goal is to keep all other microbes other than your genotype out of your space, then there is no collateral damage.

We all read about super bacterias (no antibiotic can stop them). And liek we all know this is the result of to much using antibiotics. (people used antibiotics until they felt better and then stopped. Bacteria survived and in time became imune to them). So what can we do now? First we must stop using medications for every little hedache etc. we have. Second use medications wisely. Third spend your money on something else not on medications!!

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No matter what, antibiotics is slowly being less effective against bacteria and more superbacteria emerge everyday. I think that we need to speed up research in other ways to fight bacteria such as destroying their quorum sensing mechanism.

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