Identification and Characterization of Type II Toxin-Antitoxin Systems in the Opportunistic Pathogen Acinetobacter baumannii

Abstract

Acinetobacter baumannii is an opportunistic pathogen that causes nosocomial infections. Due to the ability to persist in the clinical environment and rapidly acquire antibiotic resistance, multidrug-resistant A. baumannii clones have spread in medical units in many countries in the last decade. The molecular basis of the emergence and spread of the successful multidrug-resistant A. baumannii clones is not understood. Bacterial toxin-antitoxin (TA) systems are abundant genetic loci harbored in low-copynumber plasmids and chromosomes and have been proposed to fulfill numerous functions, from plasmid stabilization to regulation of growth and death under stress conditions. In this study, we have performed a thorough bioinformatic search for type II TA systems in genomes of A. baumannii strains and estimated at least 15 possible TA gene pairs, 5 of which have been shown to be functional TA systems. Three of them were orthologs of bacterial and archaeal RelB/RelE, HicA/HicB, and HigB/HigA systems, and others were the unique SplT/SplA and CheT/CheA TA modules. The toxins of all five TA systems, when expressed in Escherichia coli, inhibited translation, causing RNA degradation. The HigB/HigA and SplT/SplA TA pairs of plasmid origin were highly prevalent in clinical multidrug-resistant A. baumannii isolates from Lithuanian hospitals belonging to the international clonal lineages known as European clone I (ECI) and ECII.

The HigB/HigA toxin/antitoxin system of Pseudomonas aeruginosa influences the virulence factors pyochelin, pyocyanin, and biofilm formation

“…HigB functions as an endoribonuclease in Proteus spp. (Hurley andWoychik 2009), V. cholera (Christensen-Dalsgaard andGerdes 2006), A. baumanni (Jurenaite et al 2013), andE. coli K12 (Christensen-Dalsgaard et al 2010).…”

“…(Hurley and Woychik ), V. cholera (Christensen‐Dalsgaard and Gerdes ), A. baumanni (Jurenaite et al. ), and E. coli K12 (Christensen‐Dalsgaard et al. ).…”

Structure, Evolution, and Functions of Bacterial Type III Toxin-Antitoxin Systems

“…Save for a few Type I systems, all TA systems are encoded in operons wherein the antitoxin gene is usually found upstream of the toxin-encoding ORF. Nonetheless a few Type II systems such as HigBA and HicAB are exceptions and have a reverse genetic organisation [1]. This transcriptional organisation favours an excess of antitoxin in homeostatic conditions where the toxin is inhibited.…”

“…In Type II, III, and IV systems, translation of the toxin is not directly affected. Type II systems use direct protein-protein interactions where antitoxins either mask the toxin active site or sterically hinder the toxins from reaching their target [1,2,3]. Type IV antitoxins also prevent toxin-target interactions but achieve this by competing with the toxins for their target, without direct contacts with their cognate toxins [8,9].…”

The Hha-TomB Toxin-Antitoxin System Shows Conditional Toxicity and Promotes Persister Cell Formation by Inhibiting Apoptosis-Like Death in S. Typhimurium

“…Such a module, known as a toxin antitoxin (TA) system has been linked to several processes like persistence3, multidrug tolerance in bacteria4, biofilms5, stress response6, virulence578 and programmed cell death9. The toxin of a TA system that has been shown to target several cellular processes such as DNA replication, protein synthesis, RNA degradation etc., is most likely a mediator for such functions1.…”