Chemical warfare from an ecological perspective.

C weapons are recent acquisitions in humankind’s ever-growing arsenal of destruction. But bacteria and fungi have been practicing chemical warfare for a very long time. Among the numerous and structurally diverse antimicrobial agents that microbes produce are penicillin by the mold Penicillium notatum, many important antibiotics by streptomycetes, a wide range of bacteriocins by Escherichia coli and most other bacteria (including the food preservative, nisin, by Lactococcus lactis), and killer toxins by the yeast Saccharomyces cerevisiae. In this issue of PNAS, Czárán, Hoekstra, and Pagie (1) perform numerical simulations to examine the effects of these interactions on microbial diversity. They come to the surprising conclusion that all this chemical warfare may actually promote biodiversity in the microbial realm. In essence, the authors show that high levels of diversity are maintained by the complex dynamics generated when a version of the ‘‘rock-scissors-paper’’ game (2, §) is played out in a spatial context. A toxin-producing ‘‘killer’’ microbe is generally immune to the chemical agents it makes. For example, in the case of bacteriocins, the killer constitutively produces an immunity protein that binds the toxin and renders it harmless. Nonetheless, making such toxic compounds is not without costs. These costs include the material and energetic burdens of producing the toxin and maintaining immunity. Also, in some cases, the physical release of the toxin into the environment is lethal to the producing individual. In these cases, the killer is effectively a ‘‘suicide bomber’’ (3), which reminds us again of the disturbing parallels between warfare as practiced by humans and by our most primitive relations. One may wonder, in such cases, how a killer population can survive if toxin production is lethal. The explanation lies in the fact that, in a given generation, only a small fraction of the killer strain actually produces toxin (4). The presence of antimicrobial agents often selects mutations or other genetic changes that confer resistance. The emergence and spread of antibiotic-resistant pathogens in our communities and hospitals bear unfortunate witness to this evolutionary process (5). Resistant genotypes may often suffer a cost of their own, in the sense that they are inferior competitors to their sensitive counterparts in the absence of the antibiotic or toxin (6, 7). In principle, resistant strains can arise from sensitive types that lose their susceptibility to a toxin (for example, by a mutation that inactivates a receptor to which the toxin binds), or from killer strains that lose the capacity to produce a toxin but retain their immunity to it. Another important feature of microbial chemical warfare is that one finds a tremendous diversity of toxins, even within a single species. For example, there exist a multitude of colicins with which different strains of E. coli kill one another. Molecular studies of the genes that encode these bacteriocins imply a history of strong selection for innovation and change (8, 9), in essence, an evolutionary arms race. Also, toxin production and resistance functions are often encoded by genes located on transmissible, extrachromosomal elements such as plasmids. Once an innovation in chemical warfare arises in one group, it might then be acquired by another. All this implies that the means of chemical warfare among microbes are very labile from an evolutionary perspective. Many studies indicate that microbial communities are extremely diverse. For example, one analysis of the reassociation kinetics of the total bacterial DNA in a 30-g soil sample found that it contained some 20,000 common species and perhaps 500,000 rare ones (10). This diversity begs the question of how all of the different species are maintained. Ecologists have long been interested in understanding the forces that maintain diversity, although they have focused mostly on plants and animals, with little attention to microorganisms. Perhaps the simplest, and oldest, explanation is that there must exist as many different resources as there are coexisting species. But this old explanation has been supplanted by both theory and data. The existence of multiple trophic levels can maintain more distinct species than there are underlying resources. For example, two species may coexist on a single resource if there also exists a third species—a keystone predator—that preferentially preys on the superior competitor (11, 12). Two species may also coexist on one resource if its concentration fluctuates in time, such that one species is competitively superior when the resource is scarce although the other is superior when the resource is common (13, 14). Spatial variability in resource abundance, especially when coupled with differences among species in dispersal ability, also can promote biodiversity, in principle allowing an arbitrarily large number of species to persist (15, 16). In addition to direct competition for limiting resources, which ecologists call scramble competition, organisms sometimes compete by interfering with one another. Besides microbial production of toxins, other examples of interference competition include the production by some plants of compounds that they use to suppress their neighbors, and defense of territories by some animals that may prevent competitors from acquiring resources located therein. At first inspection, interference competition does not seem to be the sort of process that would help maintain diversity in an ecological community. Consider two species that compete for a single resource. Let us assume that one species is the superior competitor for the resource, but it is sensitive to a toxin that the other species produces. In a physically unstructured environment, such as a well-stirred medium, there may exist an equilibrium where both species are present, but that equilibrium is dynam-