Experimental evolution of collective β-lactam resistance in Escherichia coli via activation of a dormant outermembrane porin

Authors

Ochoa-Guerrero, A., Hollander, J., Gross, R., Batra, A., Pool, J., Reyes Marquez, F., van de Peppel, A. C., Krug, J., G.M. de Visser, J. A.

Abstract

Understanding the mechanisms that drive antibiotic resistance is relevant for both evolutionary theory and the design of effective drug therapies. A specific challenge are collective resistance mechanisms, where bacterial populations survive drug concentrations that kill individual bacteria. Here, we explore the evolvability of collective resistance mechanisms in bacterial strains expressing antibiotic-degrading {beta}-lactamases with different levels of privatization. Four strains of Escherichia coli, with or without outermembrane porin OmpF to affect drug permeability and expressing either a low or high-activity periplasmic {beta}-lactamase, were subjected to lineage selection in a gradient of the drug cefotaxime. Strains with a low-activity enzyme increased cell-level resistance, while strains with low permeability, and hence a more private {beta}-lactamase function, increased collective resistance. Remarkably, increased collective resistance in the strain with a private high-activity {beta}-lactamase came with decreased cell-level resistance. This tradeoff was primarily caused by the activation of a dormant outermembrane porin, NmpC, via the excision of an insertion sequence. Increased drug permeability through NmpC explained both its lower cell-level resistance and its greater collective resistance through faster drug removal and growth recovery via enhanced filamentation at high cell density. The recovery advantage of the NmpC mutant also explained its initial invasion within the ancestral population, suggesting that drug permeability is a readily evolvable collective-resistance mechanism in bacteria with high-activity {beta}-lactamases. Our findings highlight the role of filamentation and drug permeability in {beta}-lactamase-mediated collective resistance to these widely used drugs.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 23 Aug 2026.

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