Lon protease inactivation, or translocation of the lon gene, potentiate bacterial evolution to antibiotic resistance. Issue 6 (30th October 2013)

• Record Type: Journal Article
• Authors: Nicoloff, Hervé; Andersson, Dan I.
• Is Part Of: Molecular microbiology. Volume 90:Issue 6(2013)
• Page Start: 1233
• Page End: 1248
• Publication Date: 2013-10-30
• Subjects: Molecular microbiology -- Periodicals; 572.829
• DOI: 10.1111/mmi.12429
• Languages: English
• ISSNs: 0950-382X

Abstract

<abstract abstract-type="main"> <title>Summary</title> <p>Previous work demonstrated that selection for <italic>Escherichia coli</italic> mutants with low antibiotic resistance frequently resulted in co‐selection of <italic>lon</italic> mutations and that <italic>lon</italic><sup>−</sup> mutants evolved higher‐level resistance faster than a <italic>lon</italic><sup>+</sup> strain. Here we show that <italic>lon</italic> mutation causes a very low multidrug resistance by inducing the AcrAB‐TolC pump via stabilization of the <italic>acrAB</italic> transcriptional activators MarA and SoxS, which are substrates of the Lon protease. Fast evolution of <italic>lon</italic><sup>−</sup> mutants towards higher resistance involves selection of frequent next‐step mutations consisting of large duplications including <italic>acrAB</italic> and the mutated <italic>lon</italic> gene. Resistance results from the combined effects of <italic>acrAB</italic> duplication and <italic>lon</italic> mutation increasing dosage of efflux pump. In contrast, when <italic>acrAB</italic> duplication occurs as the first step mutation, increased Lon activity caused by <italic>lon</italic><sup>+</sup> co‐duplication mitigates the effect of <italic>acrAB</italic> duplication on resistance, and faster evolution towards higher resistance is not observed. As predicted, when the functional <italic>lon</italic> gene is relocated far from <italic>acrAB</italic> to prevent their co‐duplication, first‐step <italic>acrAB</italic> 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.</p> </abstract>