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 :
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.
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.