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Relationship between Tolerance and Persistence Mechanisms in Acinetobacter baumannii Strains with AbkAB Toxin-Antitoxin System.

ABSTRACT: The molecular mechanisms of tolerance and persistence associated with several compounds in Acinetobacter baumannii clinical isolates are unknown. Using transcriptomic and phenotypic studies, we found a link between mechanisms of bacterial tolerance to chlorhexidine and the development of persistence in the presence of imipenem in an A. baumannii strain belonging to clinical clone ST-2 (OXA-24 ?-lactamase and AbkAB toxin-antitoxin [TA] system carried in a plasmid). Interestingly, the strain A. baumannii ATCC 17978 (AbkAB TA system from plasmid) showed persistence in the presence of imipenem and chlorhexidine.

SUBMITTER: Fernandez-Garcia L

PROVIDER: S-EPMC5923160 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Relationship between Tolerance and Persistence Mechanisms in Acinetobacter baumannii Strains with AbkAB Toxin-Antitoxin System.

Fernández-García Laura L Fernandez-Cuenca Felipe F Blasco Lucía L López-Rojas Rafael R Ambroa Anton A Lopez María M Pascual Álvaro Á Bou Germán G Tomás María M

Antimicrobial agents and chemotherapy 20180426 5

The molecular mechanisms of tolerance and persistence associated with several compounds in Acinetobacter baumannii clinical isolates are unknown. Using transcriptomic and phenotypic studies, we found a link between mechanisms of bacterial tolerance to chlorhexidine and the development of persistence in the presence of imipenem in an A. baumannii strain belonging to clinical clone ST-2 (OXA-24 β-lactamase and AbkAB toxin-antitoxin [TA] system carried in a plasmid). Interestingly, th ...[more]

PMID: 29463538

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Relationship between tolerance and persistence mechanisms in Acinetobacter baumannii strains with AbkAB Toxin-Antitoxin system

Project description:Unknown are the mechanisms of tolerance and persistence associated to several compounds in A.baumannii clinical isolates. Using transcriptomical and microbiological studies, we found a link between bacterial tolerance mechanisms to clorhexidine as well as the development of persistence in presence of imipenem in an A.baumannii strain belonging to ST-2 clinical clone (carbapenem-resistant with OXA-24 ß-lactamase and AbkAB TA system by plasmid). Interestingly, in A.baumannii ATCC17978 strain (carbapenem-susceptible isolate which carries AbkAB TA system by plasmid) showed persistence in presence of imipenem.

2018-02-09 | GSE110207 | GEO

Relationship between tolerance and persistence mechanisms in Acinetobacter baumannii strains with AbkAB Toxin-Antitoxin system

Project description:Relationship between tolerance and persistence mechanisms in Acinetobacter baumannii strains with AbkAB Toxin-Antitoxin system

| PRJNA433173 | ENA

Genomics-guided identification of a conserved CptBA-like toxin-antitoxin system in Acinetobacter baumannii.

Project description:IntroductionToxin-antitoxin (TA) systems are widespread among bacteria, archaea and fungi. They are classified into six types (I-VI) and have recently been proposed as novel drug targets.ObjectivesThis study aimed to screen the pathogen Acinetobacter baumannii, known for its alarming antimicrobial resistance, for TA systems and identified a CptBA-like type IV TA, one of the least characterized systems.MethodsIn silico methods included secondary structure prediction, comparative genomics, multiple sequence alignment, and phylogenetic analysis, while in vitro strategies included plasmid engineering and expression of the TA system in Escherichia coli BL21, growth measurement, and transcription analysis with quantitative reverse-transcription polymerase chain reaction.ResultsComparative genomics demonstrated the distribution of CptBA-like systems among Gram-negative bacteria, while phylogenetic analysis delineated two major groups, in each of which Acinetobacter spp. proteins clustered together. Sequence alignment indicated the conservation of cptA and cptB in 4,732 strains of A. baumannii in the same syntenic order. Using A. baumannii recombinant cptA and cptB, cloned under different promoters, confirmed their TA nature, as cptB expression was able to reverse growth inhibition by CptA in a dose-time dependent manner. Furthermore, transcriptional analysis of cptBA in clinical and standard A. baumannii strains demonstrated the downregulation of this system under oxidative and antibiotic stress.ConclusionCombining in silico and in vitro studies confirmed the predicted TA nature of a cptBA-like system in A. baumannii . Transcriptional analysis suggests a possible role of cptBA in response to antibiotics and stress factors in A. baumannii, making it a promising drug target.

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Molecular Study of Acinetobacter baumannii that Lacking Some Essentials Genes Responsible of Toxin-Antitoxin System.

Project description:Acinetobacter genus has various species that are widespread in different environments and can exist in non-living environment samples as well. Acinetobacter baumannii (A. baumannii) is known to be one of the main causes of nosocomial infection. Few studies have examined the possibility of the presence of this opportunistic pathogen in non-living environment samples. In this study, A. baumannii strain cl-2 was isolated from dishwasher basket samples and it was identified by 16S ribosomal RNA sequencing analysis. The present study also investigated the presence of some important genes responsible for toxin-antitoxin (TA) systems necessary for the resistance of this bacterium in improper environmental conditions. Additionally, attempts were made to study some essential virulence factors, such as hemolysin, lipase, protease, and lecithinase production, as well as biofilm formation and surface motility. The findings revealed that the isolate belongs to the A. baumannii strain cl-2. The isolate was deposed in the National Center for Biotechnology Information, (NCBI) and the data can be accessed via the NCBI accession number (MW642251). The results of screening the TA system by higBA, mazEF, and relBE genes showed the isolate did not contain these genes. The hemolysin toxin activity (phenotypic test) was performed by using the streaking and spot methods on blood agar. It was found that the A. baumannii strain cl-2 had the ability to hemolyze red blood cells and produce lecithinase and protease enzymes. Finally, it was revealed that the A. baumannii strain cl-2 had surface motility based on the concentric diffusion ring of growth observed on Luria Broth agar (0.3%). In conclusion, the isolates under study showed association patterns between their ability to produce hemolysin, lipase, lecithinase, as well as protease, and other virulence factors, including surface motility and biofilm formation.

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Identification and characterization of type II toxin-antitoxin systems in the opportunistic pathogen Acinetobacter baumannii.

Project description: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-copy-number 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.

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The higBA Toxin-Antitoxin Module From the Opportunistic Pathogen Acinetobacter baumannii - Regulation, Activity, and Evolution.

Project description:Acinetobacter baumannii is one of the major causes of hard to treat multidrug-resistant hospital infections. A. baumannii features contributing to its spread and persistence in clinical environment are only beginning to be explored. Bacterial toxin-antitoxin (TA) systems are genetic loci shown to be involved in plasmid maintenance and proposed to function as components of stress response networks. Here we present a thorough characterization of type II system of A. baumannii, which is the most ubiquitous TA module present in A. baumannii plasmids. higBA of A. baumannii is a reverse TA (the toxin gene is the first in the operon) and shows little homology to other TA systems of RelE superfamily. It is represented by two variants, which both are functional albeit exhibit strong difference in sequence conservation. The higBA2 operon is found on ubiquitous 11 Kb pAB120 plasmid, conferring carbapenem resistance to clinical A. baumannii isolates and represents a higBA variant that can be found with multiple sequence variations. We show here that higBA2 is capable to confer maintenance of unstable plasmid in Acinetobacter species. HigB2 toxin functions as a ribonuclease and its activity is neutralized by HigA2 antitoxin through formation of an unusually large heterooligomeric complex. Based on the in vivo expression analysis of gfp reporter gene we propose that HigA2 antitoxin and HigBA2 protein complex bind the higBA2 promoter region to downregulate its transcription. We also demonstrate that higBA2 is a stress responsive locus, whose transcription changes in conditions encountered by A. baumannii in clinical environment and within the host. We show elevated expression of higBA2 during stationary phase, under iron deficiency and downregulated expression after antibiotic (rifampicin) treatment.

| S-EPMC5906591 | biostudies-literature

Characterizing Acinetobacter baumannii desiccation tolerance.

Project description:Desiccation tolerance has been implicated as an important characteristic that potentiates the spread of the bacterial pathogen Acinetobacter baumannii through hospitals on dry surfaces. Despite the potential importance of this stress response, scarce information is available describing the underlying mechanisms of A. baumannii desiccation tolerance. Here we characterize the factors influencing desiccation survival of A. baumannii. At the macroscale level, we find that desiccation tolerance is influenced by cell density, growth phase, and desiccation medium. Our transcriptome analysis indicates that desiccation represents a unique state for A. baumannii compared to commonly studied growth conditions and strongly influences pathways responsible for proteostasis. Remarkably, we find that an increase in total cellular protein aggregates, which is often considered deleterious, correlates positively with the ability of A. baumannii to survive desiccation. We show that artificially inducing protein aggregate formation increases desiccation survival, and more importantly, that proteins incorporated into cellular aggregates can retain activity. Our results suggest that protein aggregates may promote desiccation tolerance in A. baumannii through preserving and protecting proteins from damage during desiccation until rehydration occurs.

2018-10-27 | GSE111383 | GEO

Mechanisms of Tolerance and Resistance to Chlorhexidine in Clinical Strains of Klebsiella pneumoniae Producers of Carbapenemase: Role of New Type II Toxin-Antitoxin System, PemIK.

Project description:Although the failure of antibiotic treatment is normally attributed to resistance, tolerance and persistence display a significant role in the lack of response to antibiotics. Due to the fact that several nosocomial pathogens show a high level of tolerance and/or resistance to chlorhexidine, in this study we analyzed the molecular mechanisms associated with chlorhexidine adaptation in two clinical strains of Klebsiella pneumoniae by phenotypic and transcriptomic studies. These two strains belong to ST258-KPC3 (high-risk clone carrying β-lactamase KPC3) and ST846-OXA48 (low-risk clone carrying β-lactamase OXA48). Our results showed that the K. pneumoniae ST258-KPC3CA and ST846-OXA48CA strains exhibited a different behavior under chlorhexidine (CHLX) pressure, adapting to this biocide through resistance and tolerance mechanisms, respectively. Furthermore, the appearance of cross-resistance to colistin was observed in the ST846-OXA48CA strain (tolerant to CHLX), using the broth microdilution method. Interestingly, this ST846-OXA48CA isolate contained a plasmid that encodes a novel type II toxin/antitoxin (TA) system, PemI/PemK. We characterized this PemI/PemK TA system by cloning both genes into the IPTG-inducible pCA24N plasmid, and found their role in persistence and biofilm formation. Accordingly, the ST846-OXA48CA strain showed a persistence biphasic curve in the presence of a chlorhexidine-imipenem combination, and these results were confirmed by the enzymatic assay (WST-1).

| S-EPMC7551900 | biostudies-literature

MqsR/MqsA Toxin/Antitoxin System Regulates Persistence and Biofilm Formation in Pseudomonas putida KT2440.

Project description:Bacterial toxin/antitoxin (TA) systems have received increasing attention due to their prevalence, diverse structures, and important physiological functions. In this study, we identified and characterized a type II TA system in a soil bacterium Pseudomonas putida KT2440. This TA system belongs to the MqsR/MqsA family. We found that PP_4205 (MqsR) greatly inhibits cell growth in P. putida KT2440 and Escherichia coli, the antitoxin PP_4204 (MqsA) neutralizes the toxicity of the toxin MqsR, and the two genes encoding them are co-transcribed. MqsR and MqsA interact with each other directly in vivo and MqsA is a negative regulator of the TA operon through binding to the promoter. Consistent with the MqsR/MqsA pair in E. coli, the binding of the toxin MqsR to MqsA inhibits the DNA binding ability of MqsA in P. putida KT2440. Disruption of the mqsA gene which induces mqsR expression increases persister cell formation 53-fold, while overexpressing mqsA which represses mqsR expression reduces persister cell formation 220-fold, suggesting an important role of MqsR in persistence in P. putida KT2440. Furthermore, both MqsR and MqsA promote biofilm formation. As a DNA binding protein, MqsA can also negatively regulate an ECF sigma factor AlgU and a universal stress protein PP_3288. Thus, we revealed an important regulatory role of MqsR/MqsA in persistence and biofilm formation in P. putida KT2440.

| S-EPMC5422877 | biostudies-literature

Staphylococcus aureus toxin-antitoxin system

Project description:Type I toxin-antitoxin (TA) systems are widespread genetic modules in bacterial genomes. They express toxic peptides whose overexpression leads to growth arrest or cell death, whereas antitoxins regulate the expression of toxins, acting as labile antisense RNAs. The Staphylococcus aureus (S. aureus) genome contains and expresses several functional type I TA systems, but their biological functions remain unclear. Here we addressed and challenged experimentally, by proteomics, if a type I TA system, the SprF1/SprG1 pair, influences the overall gene expression in S. aureus. Deleted and complemented S. aureus strains were analyzed for their proteomes, both intracellular and extracellular, during growth. Comparison of intracellular proteomes between the strains points on SprF1 antitoxin as an agent downregulating protein expression. In the strain naturally expressing the SprG1 toxin, cytoplasmic proteins are excreted into the medium, but this is not due to unspecific cell leakages. Such toxin-driven release of the cytoplasmic proteins may modulate the host inflammatory response that, in turn, may amplify the S. aureus infection spread.

2021-07-05 | PXD023449 | Pride

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