Journal
MOLECULAR MICROBIOLOGY
Volume 90, Issue 6, Pages 1233-1248Publisher
WILEY-BLACKWELL
DOI: 10.1111/mmi.12429
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Funding
- Swedish Research Council [K2013-56X-13025-15-5]
- Swedish Governmental Agency for Innovation Systems [P35553]
- Swedish Foundation for Strategic Research [RBa08-0063]
- EU (EvoTAR) [282004]
- Swedish Foundation for Strategic Research (SSF) [RBa08-0063] Funding Source: Swedish Foundation for Strategic Research (SSF)
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Previous work demonstrated that selection for Escherichia coli mutants with low antibiotic resistance frequently resulted in co-selection of lon mutations and that lon(-) mutants evolved higher-level resistance faster than a lon(+) strain. Here we show that lon mutation causes a very low multidrug resistance by inducing the AcrAB-TolC pump via stabilization of the acrAB transcriptional activators MarA and SoxS, which are substrates of the Lon protease. Fast evolution of lon(-) mutants towards higher resistance involves selection of frequent next-step mutations consisting of large duplications including acrAB and the mutated lon gene. Resistance results from the combined effects of acrAB duplication and lon mutation increasing dosage of efflux pump. In contrast, when acrAB duplication occurs as the first step mutation, increased Lon activity caused by lon(+) co-duplication mitigates the effect of acrAB duplication on resistance, and faster evolution towards higher resistance is not observed. As predicted, when the functional lon gene is relocated far from acrAB to prevent their co-duplication, first-step acrAB duplication confers higher resistance, which then allows selection of frequent next-step mutations and results in faster evolution towards higher resistance. Our results demonstrate how order of appearance of mutations and gene location can influence the rate of resistance evolution.
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