Abstract
Toxin–antitoxin (TA) systems are key regulators of bacterial persistence, a multidrug-tolerant state found in bacterial species that is a major contributing factor to the growing human health crisis of antibiotic resistance. Type II TA systems consist of two proteins, a toxin and an antitoxin; the toxin is neutralized when they form a complex. The ratio of antitoxin to toxin is significantly greater than 1.0 in the susceptible population (non-persister state), but this ratio is expected to become smaller during persistence. Analysis of multiple datasets (RNA-seq, ribosome profiling) and results from translation initiation rate calculators reveal multiple mechanisms that ensure a high antitoxin-to-toxin ratio in the non-persister state. The regulation mechanisms include both translational and transcriptional regulation. We classified E. coli type II TA systems into four distinct classes based on the mechanism of differential protein production between toxin and antitoxin. We find that the most common regulation mechanism is translational regulation. This classification scheme further refines our understanding of one of the fundamental mechanisms underlying bacterial persistence, especially regarding maintenance of the antitoxin-to-toxin ratio.
Highlights
Persistence is a metabolically inactive state that enables many bacterial species to maintain a subpopulation of cells that can survive harsh changes in the environment [1,2]
We find that these classes of TA systems all have mechanisms in place to ensure sufficient production of antitoxin protein relative to toxin protein, though the details vary from class to class
The protein synthesis rates of HicAB could not be determined by the Li et al (2014) data due to low expression of this system, but our RNA sequencing (RNA-seq) analysis shows that the HicAB system has less than a two-fold difference in mRNA expression, like Class 1
Summary
Persistence is a metabolically inactive state that enables many bacterial species to maintain a subpopulation of cells that can survive harsh changes in the environment [1,2]. From a human health standpoint, persister cells are a growing problem since the metabolic dormancy that characterizes the persister state results in the persister population being multidrug-tolerant and a major contributing factor to ineffective antibiotic treatments. Evidence suggests that TA systems trigger persistence when rare events allow active toxins to accumulate and affect metabolic dormancy by slowing processes such as translation and transcription. A variety of bacterial species have TA systems, which are classified into types based on the mechanism the antitoxin uses to neutralize its cognate toxin [8,9,10,11]. Type II TA systems are the Toxins 2017, 9, 211; doi:10.3390/toxins9070211 www.mdpi.com/journal/toxins
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