Widening the spaces of selection: evolution along sublethal antimicrobial gradients

Abstract

The work of Gullberg et al. (E. Gullberg, L. M. Albrecht, C. Karlsson, L. Sandegren, D. I. Andersson, mBio 5:e01918-14, 2014) indicates that extremely low concentrations of antibiotics and heavy metals are able to compensate for the cost of harboring a plasmid encoding resistances to these inhibitors. Therefore, the "spaces of selection" for plasmids encoding antibiotic or metal resistance along gradients of antimicrobial agents might be huge, and in wide spaces a high number of bacterial cells are exposed to the selective effects. These spaces are even broader if several inhibitors are simultaneously present. Probably very small inhibitor concentrations in the environment, including in sewage and other water bodies, are sufficient to ensure the maintenance and spread of this kind of multiresistance plasmid.

FIG 1

Bacterial populations on antimicrobial gradients. Lines represent the selective effects of a gradient of antibiotic or metal concentrations, diffusing up to down. (A) When bacteria are exposed to particular (stressful) points of the gradient (top), they may adapt to different neighbor concentrations without any genetic change (phenotypic adaptation), in a way deconstructing segments of the gradient locally (down) which facilitates local replication, and eventually inheritable adaptation. (B) Down in the gradient, the fitness of bacteria carrying a resistance-encoding plasmid exposed to subminimal antibiotic concentrations (MAC) is not affected by the antimicrobial (blue ovals), and therefore the plasmid is of no benefit, imposing only cost for the host cell, resulting in no selection for maintenance and plasmid loss (blue ovals move to white ovals). Bacterial fitness decreases when MAC is slightly surpassed, and harboring a plasmid might impose an extra fitness cost, eventually resulting in even more plasmid loss (more white ovals near the MAC). Up in the gradient, the antimicrobial imposes increased fitness costs, and at a particular concentration, the MPmC (minimal plasmid maintenance concentration, named MSC in the article by Gullberg et al. [1]), the extra cost of harboring the plasmid starts to be compensated for by the advantages provided in terms of resistance to antimicrobials (antibiotics and/or metals), and the plasmid-carrying population starts to be selected (yellow ovals; the number of piled ovals represents selection). Beyond the MIC of the plasmid-free population, selection of plasmid-bearing cells reaches a maximum (red ovals) and the relative cost of harboring the plasmid reaches a minimum. At very high antimicrobial concentrations, over the minimal bactericidal concentration (MBC), the bacterial population is extinguished (black ovals). (C) Concentric circles represent an apical view of the gradient. (Left) Spaces of selection of bacteria maintaining the plasmid when exposed to a single antimicrobial. (Right) The spaces of selection are broadened when the gradient involves two antimicrobials (e.g., metals plus antibiotics), resulting in an absolute increase in cells harboring a multiresistance plasmid.