Adaptive modulation of antibiotic resistance through intragenomic coevolution

Abstract

Bacteria gain antibiotic resistance genes by horizontal acquisition of mobile genetic elements (MGE) from other lineages. Newly acquired MGEs are often poorly adapted causing intragenomic conflicts, resolved by compensatory adaptation of the chromosome, the MGE or reciprocal coadaptation. The footprints of such intragenomic coevolution are present in bacterial genomes, suggesting an important role promoting genomic integration of horizontally acquired genes, but direct experimental evidence of the process is limited. Here we show adaptive modulation of tetracycline resistance via intragenomic coevolution between Escherichia coli and the multi-drug resistant (MDR) plasmid RK2. Tetracycline treatments, including monotherapy or combination therapies with ampicillin, favoured de novo chromosomal resistance mutations coupled with mutations on RK2 impairing the plasmid-encoded tetracycline efflux-pump. These mutations together provided increased tetracycline resistance at reduced cost. Additionally, the chromosomal resistance mutations conferred cross-resistance to chloramphenicol. Reciprocal coadaptation was not observed under ampicillin-only or no antibiotic selection. Intragenomic coevolution can create genomes comprised of multiple replicons that together provide high-level, low-cost resistance, but the resulting co-dependence may limit the spread of coadapted MGEs to other lineages.

Migration promotes plasmid stability under spatially heterogeneous positive selection

“…In extreme cases, compensatory mutations can be costly in the absence of the plasmid even in the environment where they evolved [35]. Similarly, some compensatory mutations are beneficial only in the absence of positive selection [36,37], for example where the cost of the plasmid is linked to the expression of its beneficial trait [38]; under this scenario the effects of migration on the spread of compensatory mutations may be limited. Thus, pleiotropic effects of compensatory mutations may lead to compensated emigrants being at a disadvantage in their new environment, limiting their dissemination.…”

Competitive species interactions constrain abiotic adaptation in a bacterial soil community

“…Differences in tellurite inhibition were analyzed by comparing areas under the curve (Bottery et al. ), or calculating the zone of inhibition using ImageJ, while growth in minimal acetate was analyzed as . In each of these cases, data were analyzed in an LMM using actP status as a fixed effect and clone as a random effect.…”

Microbial Evolutionary Medicine – from theory to clinical practice

“…Increasingly, genomic approaches are used to track plasmid dissemination (e.g. 29), and a cohesive view of both core and accessory genomic components is needed to fully understand pathogen evolution, transmission, and virulence (30). Looking beyond the core genome raises the question whether the microbe is merely a vector of disease, in cases where virulence and antibiotic resistance stem from transferable mobile elements (31,32).…”

“…Approaches aimed at identifying resistance should not only focus on specific resistance genes, but should also consider mutations in non-coding sequences (e.g. promoters and intergenic regions) and in coding sequences (30). In E.coli ST131, the uptake of mobile elements involved in resistance was found to lead to selection for compensatory mutations in the genome (56).…”