RESEARCH ARTICLE Adaptive Resistance in Bacteria Requires Epigenetic Inheritance, Genetic Noise, and Cost of Efflux Pumps

Adaptive resistance emerges when populations of bacteria are subjected to gradual in-creases of antibiotics. It is characterized by a rapid emergence of resistance and fast re-versibility to the non-resistant phenotype when the antibiotic is removed from the medium. Recent work shows that adaptive resistance requires epigenetic inheritance and heteroge-neity of gene expression patterns that are, in particular, associated with the production of porins and efflux pumps. However, the precise mechanisms by which inheritance and vari-ability govern adaptive resistance, and what processes cause its reversibility remain un-clear. Here, using an efflux pump regulatory network (EPRN) model, we show that the following three mechanisms are essential to obtain adaptive resistance in a bacterial popu-lation: 1) intrinsic variability in the expression of the EPRN transcription factors; 2) epigenet-ic inheritance of the transcription rate of EPRN associated genes; and 3) energetic cost of the efflux pumps activity that slows down cell growth. While the first two mechanisms acting together are responsible for the emergence and gradual increase of the resistance, the third one accounts for its reversibility. In contrast with the standard assumption, our model pre-dicts that adaptive resistance cannot be explained by increased mutation rates. Our results identify the molecular mechanism of epigenetic inheritance as the main target for therapeu-tic treatments against the emergence of adaptive resistance. Finally, our theoretical frame-work unifies known and newly identified determinants such as the burden of efflux pumps that underlie bacterial adaptive resistance to antibiotics