Table 2.
Classes of phenotypic tolerance and their therapeutic implications
FeatureClass IClass II
Growth state of bacterial population Most cells replicating Most cells not replicating 
Persistence phenotype Small minority; different cells tolerate different antibiotics Large majority; same cells tolerate many antibiotics 
Inducers of persistence Unknown; stochastic Acidification, ROS, RNS, hypoxia, deprivation of C, N, P, or Fe; sublethal exposure to antibiotics 
Speculative mechanisms Epigenetic, transcriptional, translational, or posttranslational expression or suppression of any process for which genetic change can produce heritable resistance Decreased uptake, increased export, or increased catabolism of drug; metabolic stress leading to oxidative stress and adaptation; increase in proteostasis pathways; preferential transcription and translation; alternate respiratory pathways and electron acceptors 
Therapeutic implications Combine different drugs that each reach the sites of infection Include new kinds of drugs active on nonreplicating cells that reach the sites of infection 
FeatureClass IClass II
Growth state of bacterial population Most cells replicating Most cells not replicating 
Persistence phenotype Small minority; different cells tolerate different antibiotics Large majority; same cells tolerate many antibiotics 
Inducers of persistence Unknown; stochastic Acidification, ROS, RNS, hypoxia, deprivation of C, N, P, or Fe; sublethal exposure to antibiotics 
Speculative mechanisms Epigenetic, transcriptional, translational, or posttranslational expression or suppression of any process for which genetic change can produce heritable resistance Decreased uptake, increased export, or increased catabolism of drug; metabolic stress leading to oxidative stress and adaptation; increase in proteostasis pathways; preferential transcription and translation; alternate respiratory pathways and electron acceptors 
Therapeutic implications Combine different drugs that each reach the sites of infection Include new kinds of drugs active on nonreplicating cells that reach the sites of infection 

Based on Nathan (2012) and modified from Nathan and Barry (2015).

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