Where antibiotic resistance mutations meet quorum-sensing

Abstract

We do not need to rehearse the grim story of the global rise of antibiotic resistant microbes. But what if it were possible to control the rate with which antibiotic resistance evolves by de novo mutation? It seems that some bacteria may already do exactly that: they modify the rate at which they mutate to antibiotic resistance dependent on their biological environment. In our recent study [Krašovec, et al. Nat. Commun. (2014), 5, 3742] we find that this modification depends on the density of the bacterial population and cell-cell interactions (rather than, for instance, the level of stress). Specifically, the wild-type strains of Escherichia coli we used will, in minimal glucose media, modify their rate of mutation to rifampicin resistance according to the density of wild-type cells. Intriguingly, the higher the density, the lower the mutation rate (Figure 1). Why this novel density-dependent 'mutation rate plasticity' (DD-MRP) occurs is a question at several levels. Answers are currently fragmentary, but involve the quorum-sensing gene luxS and its role in the activated methyl cycle.

Keywords: DNA methylation; autoinducer 2; autoinducer 3; evolution; fluctuation test; mutagenesis; optimal control; stress-induced mutagenesis.

Figure 1. FIGURE 1: Density-dependent mutation rate plasticity in E. coli.

The green contours indicate mutation rates for E. coli with a functional Activated Methyl Cycle (AMC; green cell) across a range of population densities. In the example cells in the plot corners, a blue and red explosion indicates a mutational event resulting in a rifampicin resistant cell. The orange contours correspond to luxS deletant cells which don’t produce the signal (arrows coming from the green cell) and have an incomplete AMC (orange cell). Contours are density plots across all the data from Krašovec et al. 2014 (344 data points, 77 of which correspond to the orange contours), including both E. coli B and K12 strains and accounting for all the effects noted there (e.g., data from the complemented ΔluxS mutant are included in the green area, not the orange). Abbreviations: HCY, homocysteine; MET, methionine; SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine; SRH, S-ribosylhomocysteine.