A Game Theoretic Analysis of the Dual Function of Antibiotics

Abstract

There are two major views toward the role of antibiotics in microbial social interactions. The classical view is that antibiotics serve as weapons, produced by a bacterial species, at a significant cost, to inhibit the growth of its competitors. This view is supported by observations that antibiotics are usually upregulated by stress responses that infer the intensity of ecological competition, such as nutrient limitation and cellular damage, which point out to a competitive role for antibiotics. The other ecological function frequently assigned to antibiotics is that they serve as signaling molecules which regulate the collective behavior of a microbial community. Here, we investigate the conditions at which a weapon can serve as a signal in the context of microbial competition. We propose that an antibiotic will serve as a signal whenever a potential alteration of the growth behavior of the signal receiver, in response to a subinhibitory concentration (SIC) of the antibiotic, reduces the competitive pressure on the signal producer. This in turn would lead to avoiding triggering the stress mechanisms of the signal producer responsible for further antibiotics production. We show using individual-based modeling that this reduction of competitive pressure on the signal producer can happen through two main classes of responses by the signal recipient: competition tolerance, where the recipient reduces its competitive impact on the signal producer by switching to a low growth rate/ high yield strategy, and niche segregation, where the recipient reduces the competitive pressure on the signal producer by reducing their niche overlap. Our hypothesis proposes that antibiotics serve as signals out of their original function as weapons in order to reduce the chances of engaging in fights that would be costly to both the antibiotic producer as well as to its competitors.

Keywords: antibiotics; game theory; individual-based modeling; microbial communities; signaling theory.

Figure 1

A diagram of the competition between an antibiotic producing invader vs. a resident species, competing over a single nutrient. The change in nutrient utilization strategy by the resident species in response to competition with a nutrient stress regulated invader is examined. The diagram depicts two biological species: the invader (I) and the resident (R), both enclosed in a square, and two chemical species, a nutrient (N) and an antibiotic (A), denoted by circles. The consumption of N by I and R, as well as the production of A by I are all denoted by solid lines. The growth inhibiting effect of A on R is denoted by a dashed line. Finally, the production of A by I is regulated by nutrient stress. This is represented by a decision flowchart where I senses the nutrient concentration, this action is represented by a dotted line, and it activates the production of A only when it falls below a threshold concentration N_th.

Figure 2

Competition tolerance, no signaling scenario: the usage of a high growth rate/ low yield strategy by the resident species, while being usually an optimal competitive strategy, leads to a quick depletion of nutrients, triggering antibiotic production by the invader species and subsequent decrease in the overall population of both species. (A) A snapshot of the competition between the invader species (green) vs. the resident species (red), by the end of the simulation. (B) The evolution of the population of an antibiotic producing invader and a resident species, growing on the same nutrient. (C) The evolution of the consumption of the nutrient by the invader species (green), and the resident species (red), as well as the production of antibiotic by the invader species (black).

Figure 3

Competition tolerance, signaling scenario: by switching to low growth rate/ high yield strategy, the resident species can achieve more efficient usage of resources, avoiding triggering of the release of the expensive antibiotic by the invader, both parties avoid a costly fight. (A) A snapshot of the competition between the invader species (green) vs. the resident species (red), by the end of the simulation. (B) The evolution of the population of an antibiotic producing invader and a resident species, growing on the same nutrient, with the resident species adopting low growth rate/ high yield strategy. (C) The evolution of the consumption of the nutrient by the invader species (green), and the resident species (red), as well as the production of antibiotic by the invader species (black).

Figure 4

The fitness of the two species in no antibiotic signaling scenario vs. signaling scenario. Again signaling would be expected to be evolutionary stable here as it achieves a gain in fitness for both the sender and receiver. The asterisks represent the mean of the results of 50 simulations, while the error bars represent the standard deviation of the results.

Figure 5

A diagram of the competition between an antibiotic producing invader and a resident species, competing over a high value nutrient, N_H. While consuming the high value nutrient is the optimal growth strategy for the resident species in absence of a antibiotic producing opponent, niche segregation by switching to consuming the low value nutrient, N_L, is the optimal response when competing with such opponent, as it would avoid triggering nutrient stress regulated antibiotic release by the invader. See Figure 2 legend for an explanation of the diagram's symbols.

Figure 6

Niche segregation, no signaling scenario: in absence of signaling between the invading and resident species, the competition over the same high value nutrient leads to triggering nutrient stress antibiotic release, which damages the population of the resident species at a cost to the invader species. (A) A snapshot of the competition between the invader species (green) vs. the resident species (red), by the end of the simulation. (B) The evolution of the population of an antibiotic producing invader and a resident species, competing over a common resource. (C) The evolution of the total consumption of the two nutrients as well as the production of the antibiotic by the invader species.

Figure 7

Niche segregation, signaling scenario: when the resident species responds to an antibiotic signal from the invader species by switching to its metabolism to a low value nutrient, the further release of the antibiotic is avoided, to the benefit of both species. (A) A snapshot of the competition between the invader species (green) vs. the resident species (red), by the end of the simulation. (B) The evolution of the population of an antibiotic producing invader and a resident species, when the resident species respond to signaling by specializing in the low value nutrient. (C) The evolution of the total consumption of the two nutrients as well as the production of the antibiotic by the invader species.

Figure 8

The fitness of the two species in no antibiotic signaling scenario vs. signaling scenario. In the signaling scenario, both the invader and the resident species benefit from the evolution of a signaling mechanism. The data representation is the same as Figure 4.

Figure 9

The fitness of a non-efficient antibiotic producer vs. the resident species, when the resident species adopts a competition tolerance strategy at a low subinhibitory antibiotic concentration. While the non-efficient antibiotic producer is not capable of inflicting significant damage at the resident species, it can produce enough quantities of the antibiotic to activate the competition tolerance response of the resident species, achieving a high fitness gain in the process. The data representation is the same as Figure 4.

Figure 10

The fitness of a non-efficient antibiotic producer vs. a resident species, when the resident species adopts a competition tolerance strategy at a high subinhibitory antibiotic concentration. By setting a high signal threshold, the resident species avoid abusing its competition tolerance response by weak opponents. Here, the cost incurred by the non-efficient antibiotic producer to activate the competition tolerance response is higher than the potential gain. The data representation is the same as Figure 4.

Figure 11

The fitness of an efficient antibiotic producer vs. a resident species, at different signaling scenarios. While expensive signaling is costly for both the resident and the invader species, it ensures honest communication. The data representation is the same as Figure 4.