As most readers of this website are well aware, antibiotic resistance poses a considerable problem for public health, and we are in serious need of new approaches for dealing with this threat. One possible direction could be to use drugs such as quorum-sensing disruptors (e.g. Dong et al. 2001 Nature) that target disrupt bacterial cooperation, since coordinated cooperative behavior is necessary for many forms of pathogenesis. At the conclusion of my previous commentary, I briefly mentioned a paper in Ecology Letters by André and Godelle 2005 about the possible evolutionary benefits this approach. There, André and Godelle ask the question “How quickly will resistance evolve to drugs that target group-level cooperative traits of bacteria?”
Prior to reading this paper, I had always been somewhat pessimistic about the prospects for drugs that disrupt quorum signals, for the simple reason that I expected that bacteria could quickly evolve resistance to such compounds. All it would take to get resistance, after all, is a point mutation to constitutively express the genes that were previously regulated by the quorum sensing signals.
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But that reasoning of mine may be flawed: I was assuming that the evolution of resistance to quorum-sensing disruptors, like resistance to convention antibiotics, would usually be limited only by mutation supply. Instead, André and Godelle make a compelling and important argument that in the case of these cooperative traits, resistance evolution could also be limited by selection itself. The idea is bacterial cooperative behavior is not something that evolves trivially; bacteria need to find ways to overcome the free-rider problem associated with many forms of cooperation. Think about the first resistant mutant to a conventional antibiotic, and compare its fate with the fate of the first resistant mutant to a quorum-sensing disruptor. The first resistant mutant to a conventional antibiotic enjoys a strong selective advantage and rapidly increases in frequency. The first resistant mutant to a quorum sensing disruptor goes ahead and produces whatever molecule or behavior is normally regulated by the quorum signal, at a cost to itself – but none of its neighbors do the same, so it receives no benefits from its actions. Thus we would expect it to be selected against, at least initially.
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Moreover, if resistance to quorum sensing disruptors does evolve, it may do so at a rate set by the reproduction rate of bacterial groups rather than that of individual bacteria. As the authors state in the abstract, by “targeting treatments against adaptive properties of groups instead of individuals
we shift one level up the relevant unit of organization generating resistance. Instead of facing billions of bacteria with a very rapid evolutionary rate, these alternative treatments face a reduced number of larger organisms with a lower evolutionary [rate].” To summarize, it is quite a feat any time natural selection overcomes the cooperation problem, and once disrupted, that cooperation may take a long time to return.
To illustrate their argument, the authors put together a continuous-time branching process model of evolution in a structured population. Here, bacteria are continually dispersing and reforming new groups much as in a classic haystack model (Maynard Smith 1964). Here and there, the mathematics could probably benefit from further development. For example, to compute fixation rates and probabilities, the authors have to assume constant-state conditions for the population – and in particular, they assume that resistance is very rare within and among groups. In other words, they compute the probability of fixation, based on the assumption that fixation never occurs. This is probably not as bad as it sounds, if all of the waiting occurs early and the dynamics then proceed more or less deterministically once resistance gets well established; the authors justify their approach with this argument. In any case, these are mathematical quibbles; the basic idea seems likely to be both correct and important.
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If I were promoting quorum-sensing disruptors as antimicrobial therapies, I would certainly want to understand the implications of this article when answering questions about the evolution of resistance to my proposed therapies. I think that André and Godelle may be on to something very important here, and those of us studying resistance evolution would do well to take note.
André and Godelle (2005) Ecology Letters 8:800-810
Bassler (2002) Cell 109:421-424
Dong et al. (2001) Nature 411 813-7
National Research Council (2006) Treating Infectious Diseases in a Microbial World
Maynard Smith (1964) Nature 201:1145–1147