Nonoptimal gene expression creates latent potential for antibiotic resistance Journal Article

Author(s): Palmer, Adam C; Chait, Remy; Kishony, Roy
Article Title: Nonoptimal gene expression creates latent potential for antibiotic resistance
Affiliation IST Austria
Abstract: Bacteria regulate genes to survive antibiotic stress, but regulation can be far from perfect. When regulation is not optimal, mutations that change gene expression can contribute to antibiotic resistance. It is not systematically understood to what extent natural gene regulation is or is not optimal for distinct antibiotics, and how changes in expression of specific genes quantitatively affect antibiotic resistance. Here we discover a simple quantitative relation between fitness, gene expression, and antibiotic potency, which rationalizes our observation that a multitude of genes and even innate antibiotic defense mechanisms have expression that is critically nonoptimal under antibiotic treatment. First, we developed a pooled-strain drug-diffusion assay and screened Escherichia coli overexpression and knockout libraries, finding that resistance to a range of 31 antibiotics could result from changing expression of a large and functionally diverse set of genes, in a primarily but not exclusively drug-specific manner. Second, by synthetically controlling the expression of single-drug and multidrug resistance genes, we observed that their fitness-expression functions changed dramatically under antibiotic treatment in accordance with a log-sensitivity relation. Thus, because many genes are nonoptimally expressed under antibiotic treatment, many regulatory mutations can contribute to resistance by altering expression and by activating latent defenses.
Journal Title: Molecular Biology and Evolution
Volume: 35
Issue 11
ISSN: 15371719
Publisher: NLM  
Date Published: 2018-11-01
Start Page: 2669
End Page: 2684
DOI: 10.1093/molbev/msy163
Notes: This work was supported by US National Institutes of Health (Grant No. R01-GM081617 to R.K.); Israeli Centers of Research Excellence I-CORE Program (ISF Grant No. 152/11 to R.K.); European Research Council (FP7 ERC Grant No. 281891 to R.K.); and National Health and Medical Research Council (Early Career Fellowship 1072965 to A.C.P.).
Open access: no