Concentration-dependent activity of antibiotics in natural environments

Abstract

Bacterial responses to antibiotics are concentration-dependent. At high concentrations, antibiotics exhibit antimicrobial activities on susceptible cells, while subinhibitory concentrations induce diverse biological responses in bacteria. At non-lethal concentrations, bacteria may sense antibiotics as extracellular chemicals to trigger different cellular responses, which may include an altered antibiotic resistance/tolerance profile. In natural settings, microbes are typically in polymicrobial communities and antibiotic-mediated interactions between species may play a significant role in bacterial community structure and function. However, these aspects have not yet fully been explored at the community level. Here we discuss the different types of interactions mediated by antibiotics and non-antibiotic metabolites as a function of their concentrations and speculate on how these may amplify the overall antibiotic resistance/tolerance and the spread of antibiotic resistance determinants in a context of polymicrobial community.

Keywords: antibiotic; community; cue; interaction; resistance; signal; stress; tolerance.

FIGURE 1

A single chemical mediates different bacteria–bacteria interactions in a context of a polymicrobial community. The schematic represents how a single chemical released by one bacterial species can be perceived differently in a multispecies community. Microorganisms that benefit positively (blue) or negatively (brown) from the different interaction are represented. Arrows indicate direction of evolved pathway, e.g., an organism evolves to “sense” a cue or in some case can use an antibiotic as a nutritional source (Dantas et al., 2008). In the case of signaling and interspecies signaling, pathways from both producer and receiver cells have co-evolved to the benefit of both microorganisms. In the case of coercion or toxic interactions such as those exhibited by antibiotics, only the producer benefits from the interaction. When the producer itself detects the signal, this would be a case of quorum sensing or cell–cell signaling. In the case of antibiotics, the producer usually co-expresses resistance pathways and these can be co-expressed without a sensing circuit but often, such as with many lantibiotics, they are detected by the cell and respond in a classical quorum sensing feedback loop.

FIGURE 2

Biological responses toward antibiotics are concentration-dependent. Bacterial interactions mediated by antibiotics induce biological responses in receiver bacteria in a dose-dependent manner. The antimicrobial behavior (toxin) of antibiotics occurs when their concentrations is high leading to bacterial death or growth arrest in susceptible receiver cells. At lower concentrations, subinhibitory, antibiotics can act as stress inducers, coercions or be sensed as cues. Biological responses induced in receiver bacteria when antibiotics are at subinhibitory concentrations can affect various cellular responses or alter gene expression leading to different adaptive responses impacting antibiotic resistance/tolerance.

FIGURE 3

Biological role(s) of antibiotic resistance in natural communities. (A) The response of bacterial cells to antibiotic whether it is bactericidal/bacteriostatic or subinhibitory, the biological response (as a cue or coercion) will be shifted by antibiotic resistance. (B) In natural environments, differences in physiological states can impact the expression of antibiotic resistance or tolerance mechanisms. Antibiotic concentrations in these environments may also be distributed as gradients, meaning that the population will not necessarily respond uniformly.

FIGURE 4

Antibiotic induction of extracellular DNA (eDNA) release in a multispecies community and antibiotic tolerance. The schematic represents how two bacterial species, P. aeruginosa (green) and S. aureus (purple), respond to subinhibitory antibiotics to release eDNA. Subinhibitory antibiotics induced the production of pyocyanin (Shen et al., 2008), which is associated with increased H₂O₂ levels responsible for cell lysis and DNA release (Das and Manefield, 2012). In S. arureus, exposure to subinhibitory β-lactam antibiotics induces release of eDNA via an autolysis-dependent mechanism (Kaplan et al., 2012). The release of eDNA by both bacteria can induce antibiotic tolerance in communities (Mulcahy et al., 2008).

FIGURE 5

Metabolite-mediated interactions modulating antibiotic resistance or tolerance in polymicrobial communities. Following an antibiotic treatment, natural communities will respond, adapt, and evolve through the establishment of dynamic interactions mediated by antibiotics and non-antibiotic metabolites. A simple polymicrobial community comprising P. aeruginosa (green), S. aureus (purple), and Streptococcus spp. (brown) is used to illustrate this hypothetical scenario. A proportion of the established community, made of multispecies biofilms and planktonic cells, will die and subsequently lyse upon antibiotic exposure, unless cells harbor the corresponding antibiotic resistance determinant (capped cells; red, blue, or orange corresponding to the respective antibiotic) or are part of multicellular structures (biofilms, aggregates). Subinhibitory antibiotics and non-antibiotic metabolites within the community can subsequently induce different antibiotic tolerance mechanisms leading to an altered community in terms of composition and antibiotic resistance/tolerance.