Molecular Mechanism of Bacterial Persistence by HipA

Germain, Elsa; Castro-Roa, Daniel; Zenkin, Nikolay; Gerdes, Kenn

doi:10.1016/j.molcel.2013.08.045

Cited by 330 publications

(339 citation statements)

References 42 publications

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“…TA modules that are upregulated in persisters are terminal effectors of microbial persistence 60,61 . Ectopic overexpression of ribonucleases (RelE and MazF toxin), HipA (a glutamyl transfer RNA synthetase protein kinase) and TisB (membrane damage protein) enhances drug tolerance in bacteria 39,[62][63][64] . In E. coli, TA systems function synergistically, and the successive deletion of 10 TA systems progressively reduces persister cell formation in vitro 8 .…”

Section: Discussionmentioning

confidence: 99%

MazF ribonucleases promote Mycobacterium tuberculosis drug tolerance and virulence in guinea pigs

et al. 2015

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Toxin-antitoxin (TA) systems are highly conserved in members of the Mycobacterium tuberculosis (Mtb) complex and have been proposed to play an important role in physiology and virulence. Nine of these TA systems belong to the mazEF family, encoding the intracellular MazF toxin and its antitoxin, MazE. By overexpressing each of the nine putative MazF homologues in Mycobacterium bovis BCG, here we show that Rv1102c (MazF3), Rv1991c (MazF6) and Rv2801c (MazF9) induce bacteriostasis. The construction of various single-, double-and triple-mutant Mtb strains reveals that these MazF ribonucleases contribute synergistically to the ability of Mtb to adapt to conditions such as oxidative stress, nutrient depletion and drug exposure. Moreover, guinea pigs infected with the triple-mutant strain exhibits significantly reduced bacterial loads and pathological damage in infected tissues in comparison with parental strain-infected guinea pigs. The present study highlights the importance of MazF ribonucleases in Mtb stress adaptation, drug tolerance and virulence.

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Section: Discussionmentioning

confidence: 99%

MazF ribonucleases promote Mycobacterium tuberculosis drug tolerance and virulence in guinea pigs

et al. 2015

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“…HipA was first thought to phosphorylate the translation factor EF-Tu, leading to persistence via cell stasis (107). However, it was recently shown that HipA more likely inhibits glutamyl-tRNA synthetase (GltX) through phosphorylation and thus triggers the synthesis of ppGpp (see below) (108).…”

Section: Persisters Play a Central Role In Biofilm Recalcitrance Towamentioning

confidence: 99%

Biofilm-Related Infections: Bridging the Gap between Clinical Management and Fundamental Aspects of Recalcitrance toward Antibiotics

Lebeaux

Ghigo

Beloin

2014

Microbiol Mol Biol Rev

1,050

862

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International audienceSurface-associated microbial communities, called biofilms, are present in all environments. Although biofilms play an important positive role in a variety of ecosystems, they also have many negative effects, including biofilm-related infections in medical settings. The ability of pathogenic biofilms to survive in the presence of high concentrations of antibiotics is called "recalcitrance" and is a characteristic property of the biofilm lifestyle, leading to treatment failure and infection recurrence. This review presents our current understanding of the molecular mechanisms of biofilm recalcitrance toward antibiotics and describes how recent progress has improved our capacity to design original and efficient strategies to prevent or eradicate biofilm-related infections

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“…RelE inhibits translation by cleavage of ribosome-bound mRNAs at the ribosomal A site (20). HipA inhibits translation by phosphoryla-tion of glutamyl-tRNA synthetase (21). VapC toxins from some enteric bacteria cleave the initiator tRNA fMet (22).…”

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confidence: 99%

Structure-Function Analysis of VapB4 Antitoxin Identifies Critical Features of a Minimal VapC4 Toxin-Binding Module

2015

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T oxin-antitoxin (TA) systems were first identified to be addictive genetic elements responsible for the maintenance of plasmid stability during cell segregation (1, 2). Subsequently, chromosomally encoded TA systems were characterized to be involved in several mechanisms of toxin action (3, 4). TA systems typically consist of two elements, a toxin protein that suppresses cell growth by targeting essential cellular metabolic pathways and an antitoxin RNA or protein that binds to and blocks the growth inhibition activity of the toxin. Different types of TA systems have been defined according to the nature and modes of action of antitoxins, and of these, the type II TA systems are the most abundant and well studied (5, 6). The type II toxins-antitoxins are typically encoded in the same operon, where the gene for the antitoxin is located upstream of that for the toxin, except in the case of higBA, which has a reversed gene order (7). The type II antitoxin is a protein that directly interacts with its cognate toxin, resulting in neutralization of toxicity. The antitoxin or the toxin-antitoxin protein complex often acts as a repressor that autoregulates the transcription of TA operons via its ability to bind to the promoter (8). During cellular stress, the antitoxin is hydrolyzed by a protease, such as Lon or Clp, to release the toxin from the protein complex and derepress transcription of the TA operon (7). These properties allow TA systems to play regulatory roles in bacterial gene expression and the establishment and maintenance of dormancy. This nonreplicative state may contribute to latency.Type II TA systems are classified into several different families on the basis of sequence similarities and the functions of the toxins (7-9). CcdB and ParE inhibit DNA replication by targeting DNA gyrase (10, 11). Doc arrests translation elongation by phosphorylation of elongation factor Tu (12, 13). Kis and HicA cleave mRNA in a ribosome-independent manner (14, 15). MazF targets various RNAs, including mRNA, 16S rRNA,. RelE inhibits translation by cleavage of ribosome-bound mRNAs at the ribosomal A site (20). HipA inhibits translation by phosphoryla-

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Molecular Mechanism of Bacterial Persistence by HipA

Cited by 330 publications

References 42 publications

MazF ribonucleases promote Mycobacterium tuberculosis drug tolerance and virulence in guinea pigs

MazF ribonucleases promote Mycobacterium tuberculosis drug tolerance and virulence in guinea pigs

Biofilm-Related Infections: Bridging the Gap between Clinical Management and Fundamental Aspects of Recalcitrance toward Antibiotics

Structure-Function Analysis of VapB4 Antitoxin Identifies Critical Features of a Minimal VapC4 Toxin-Binding Module

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