A Game Theoretic Analysis of the Dual Function of Antibiotics.

Ihab Hashem,Jan F.M Van Impe

doi:10.3389/fmicb.2021.812788

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.

Highlights

When antibiotics were first discovered it was widely assumed that their ecological function in nature is similar to their observed effect in the laboratory settings, a “weapon” used by bacterial species to fight its competitors (Waksman and Woodruff, 1940)
The production of the antibiotic is regulated by a stress response such that it is only initiated when the nutrient concentration is lower than a certain threshold Nth, this condition is expressed by the Heaviside step function H(Nth − N), which is equal to one only when N < Nth
We hypothesize that owing to its original function as a weapon, an antibiotic can serve as a signal as well

Summary

Introduction

When antibiotics were first discovered it was widely assumed that their ecological function in nature is similar to their observed effect in the laboratory settings, a “weapon” used by bacterial species to fight its competitors (Waksman and Woodruff, 1940) This was challenged by observations that the concentration of antibiotics in natural contexts, soil microbiome for example, is usually lower than their inhibiting concentrations, raising doubts about their assumed function as a weapon (Yim et al, 2006; Fajardo and Martínez, 2008; Miao and Davies, 2010). It was found that SIC of antimicrobials can induce the expression of traits that are beneficial for the recipient bacteria such as cytotoxicity, biofilm formation, and motility (Linares et al, 2006) This has led to a suggestion (Linares et al, 2006) that the assumed ecological role of antibiotics should be revised: “from weapons involved in microbial struggle for life to collective regulators of the homeostasis of microbial communities” (Linares et al, 2006). An interesting example of such interaction is the rock-paperscissor dynamics where the maintenance of biological diversity is mediated by antibiotic production (Czárán et al, 2002; Baquero et al, 2019)

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Conclusion