Nonoptimal gene expression creates latent potential for antibiotic resistance

A. Palmer, R.P. Chait, R. Kishony, Molecular Biology and Evolution 35 (2018) 2669–2684.

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Journal Article | Published | English
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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.
Publishing Year
Date Published
2018-08-28
Journal Title
Molecular Biology and Evolution
Volume
35
Issue
11
Page
2669 - 2684
IST-REx-ID

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Palmer A, Chait RP, Kishony R. Nonoptimal gene expression creates latent potential for antibiotic resistance. Molecular Biology and Evolution. 2018;35(11):2669-2684. doi:10.1093/molbev/msy163
Palmer, A., Chait, R. P., & Kishony, R. (2018). Nonoptimal gene expression creates latent potential for antibiotic resistance. Molecular Biology and Evolution, 35(11), 2669–2684. https://doi.org/10.1093/molbev/msy163
Palmer, Adam, Remy P Chait, and Roy Kishony. “Nonoptimal Gene Expression Creates Latent Potential for Antibiotic Resistance.” Molecular Biology and Evolution 35, no. 11 (2018): 2669–84. https://doi.org/10.1093/molbev/msy163.
A. Palmer, R. P. Chait, and R. Kishony, “Nonoptimal gene expression creates latent potential for antibiotic resistance,” Molecular Biology and Evolution, vol. 35, no. 11, pp. 2669–2684, 2018.
Palmer A, Chait RP, Kishony R. 2018. Nonoptimal gene expression creates latent potential for antibiotic resistance. Molecular Biology and Evolution. 35(11), 2669–2684.
Palmer, Adam, et al. “Nonoptimal Gene Expression Creates Latent Potential for Antibiotic Resistance.” Molecular Biology and Evolution, vol. 35, no. 11, NLM , 2018, pp. 2669–84, doi:10.1093/molbev/msy163.

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