Experimental evolution of collective β-lactam resistance in Escherichia coli via activation of a dormant outermembrane porin
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…
Collective antibiotic resistance in bacterial populations is a growing concern that poses challenges to both evolutionary biology and drug therapy development. In this study, the researchers investigated the evolvability of collective resistance mechanisms in certain strains of Escherichia coli capable of producing antibiotic-degrading beta-lactamases.
They used four different E. coli strains, some with a membrane protein (OmpF) affecting drug permeability and either a beta-lactamase enzyme of low or high activity to explore these mechanisms.
Under conditions of changing drug concentration using cefotaxime, the researchers found that strains with low enzyme activity demonstrated increased resistance at the cell level, while strains with lower drug permeability, resulting in a more private function of the beta-lactamase, showed increased collective resistance. A surprising finding was that strains with a highly active beta-lactamase and a more private function experienced a trade-off: they had decreased cell-level resistance but increased collective resistance.
This tradeoff was primarily due to the activation of a dormant outermembrane porin (NmpC) triggered by the excision of an insertion sequence. The increased drug permeability through NmpC led to two important outcomes. Firstly, it resulted in lower cell-level resistance. Secondly, it facilitated faster drug removal and growth recovery through enhanced filamentation at high cell density, ultimately contributing to its greater collective resistance.
The improved recovery advantage of the NmpC mutant also played a crucial role in its initial invasion within the ancestral population. This observation indicates that drug permeability is a readily evolvable collective-resistance mechanism in bacteria that possess high-activity beta-lactamases. The findings of this study underscore the significance of filamentation and drug permeability in beta-lactamase-mediated collective resistance to antibiotics, which are commonly used in clinical settings.
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