The toxin from a ParDE toxin‐antitoxin system found in Pseudomonas aeruginosa offers protection to cells challenged with anti‐gyrase antibiotics.

Summary: Toxin‐antitoxin systems are mediators of diverse activities in bacterial physiology. For the ParE‐type toxins, their reported role of gyrase inhibition utilized during plasmid‐segregation killing indicates they are toxic. However, their location throughout chromosomes leads to questions about function, including potential non‐toxic outcomes. The current study has characterized a ParDE system from the opportunistic human pathogen Pseudomonas aeruginosa (Pa). We identified a protective function for this ParE toxin, PaParE, against effects of quinolone and other antibiotics. However, higher concentrations of PaParE are themselves toxic to cells, indicating the phenotypic outcome can vary based on its concentration. Our assays confirmed PaParE inhibition of gyrase‐mediated supercoiling of DNA with an IC50 value in the low micromolar range, a species‐specificity that resulted in more efficacious inhibition of Escherichia coli derived gyrase versus Pa gyrase, and overexpression in the absence of antitoxin yielded an expected filamentous morphology with multi‐foci nucleic acid material. Additional data revealed that the PaParE toxin is monomeric and interacts with dimeric PaParD antitoxin with a KD in the lower picomolar range, yielding a heterotetramer. This work provides novel insights into chromosome‐encoded ParE function, whereby its expression can impart partial protection to cultures from selected antibiotics. The gene pa0124 encodes a ParE‐type toxin that can inhibit DNA gyrase. While high concentrations mediate toxicity by inhibiting gyrase, leading to dsDNA breaks, low concentrations offer some protection against antibiotics, particularly those that target DNA gyrase. This is a unique spectrum of phenotypic outcomes for the ParE toxin family highlighting concentration‐dependent protective to deleterious functions. [ABSTRACT FROM AUTHOR]