Collective antibiotic resistance: mechanisms and implications

Abstract

In collective resistance, microbial communities are able to survive antibiotic exposures that would be lethal to individual cells. In this review, we explore recent advances in understanding collective resistance in bacteria. The population dynamics of 'cheating' in a system with cooperative antibiotic inactivation have been described, providing insight into the demographic factors that determine resistance allele frequency in bacteria. Extensive work has elucidated mechanisms underlying collective resistance in biofilms and addressed questions about the role of cooperation in these structures. Additionally, recent investigations of 'bet-hedging' strategies in bacteria have explored the contributions of stochasticity and regulation to bacterial phenotypic heterogeneity and examined the effects of these strategies on community survival.

Figure 1. Enzymatic inactivation of antibiotics allows cooperative resistance

(a) When a resistance enzyme (blue) is expressed (from a resistance plasmid, red), the amount of antibiotic (green squares) inside the cell is determined by the balance between flux and inactivation (inactivated antibiotic, green 3/4 square). If the intracellular concentration is below some critical threshold at a given external concentration of drug, the cells will survive and grow; otherwise, the cells will die. (b) The outcome of antibiotic treatment depends on cell density and resistance enzyme production. Starting resistant cell density determines whether the population will be able to inactivate enough of the drug to allow re-growth before it is driven to extinction. (c) This results in density-dependent changes in the external concentration of drug that is sufficient to prevent re-growth (called the minimum inhibitory concentration or MIC), characteristic of the inoculum effect. (d) Cooperative inactivation can protect sensitive cells which do not carry the resistance gene, and the population structure after re-growth may be very different from the starting structure due to fitness differences between sensitive cells and cells expressing the resistance enzyme.

Figure 2. Mechanisms of collective resistance in biofilms

Within the static structure of a biofilm, multiple mechanisms may contribute to community resistance. (a) The matrix itself may act as a diffusion barrier, preventing the drug (green squares) from reaching its target. (b) Enzymatic inactivation by bacteria near the surface of the film (white layer) can protect sensitive bacteria deeper within the structure. In the deep layers of a biofilm (dark pink layer), diffusion gradients will produce a hostile environment where (c) the drug itself may lose efficacy (blue squares) and (d) the member bacteria of the biofilm may enter altered metabolic states (red cells) inimical to antibiotic action.

Figure 3. Phenotypic heterogeneity is produced by underlying stochasticity and environmental information

In a population of genetically identical cells, phenotypic variants emerge as a result of stochastic switching (black cells, left) and responsive switching (red cells, right) after detection of environmental changes or chemical signals (blue hexagons). When the environment becomes stressful, cells that have undergone phenotypic switching are able to endure and thereby gain fitness relative to their undifferentiated clonemates.