Stringent response protein as a potential target to intervene persistent bacterial infection

Kushwaha, G.S.; Oyeyemi, Bolaji Fatai; Bhavesh, Neel Sarovar

doi:10.1016/j.biochi.2019.07.006

Cited by 29 publications

(34 citation statements)

References 98 publications

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“…One such mechanism is the stringent response -a near-universal stress response orchestrated by hyper-phosphorylated derivatives of housekeeping nucleotides GDP and GTP: guanosine tetraphosphate (ppGpp) and guanosine pentaphosphate (pppGpp), collectively referred to as (p)ppGpp (Hauryliuk et al, 2015;Liu et al, 2015;Steinchen and Bange, 2016). Since the stringent response and (p)ppGpp-mediated signaling are implicated in virulence, antibiotic resistance and tolerance (Dalebroux et al, 2010;Dalebroux and Swanson, 2012;Hauryliuk et al, 2015), this stress signaling system has been recently targeted for development of new anti-infective compounds (Kushwaha et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

The C-Terminal RRM/ACT Domain Is Crucial for Fine-Tuning the Activation of ‘Long’ RelA-SpoT Homolog Enzymes by Ribosomal Complexes

et al. 2020

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The (p)ppGpp-mediated stringent response is a bacterial stress response implicated in virulence and antibiotic tolerance. Both synthesis and degradation of the (p)ppGpp alarmone nucleotide are mediated by RelA-SpoT Homolog (RSH) enzymes which can be broadly divided in two classes: single-domain 'short' and multi-domain 'long' RSH. The regulatory ACT (Aspartokinase, Chorismate mutase and TyrA)/RRM (RNA Recognition Motif) domain is a near-universal C-terminal domain of long RSHs. Deletion of RRM in both monofunctional (synthesis-only) RelA as well as bifunctional (i.e., capable of both degrading and synthesizing the alarmone) Rel renders the long RSH cytotoxic due to overproduction of (p)ppGpp. To probe the molecular mechanism underlying this effect we characterized Escherichia coli RelA and Bacillus subtilis Rel RSHs lacking RRM. We demonstrate that, first, the cytotoxicity caused by the removal of RRM is counteracted by secondary mutations that disrupt the interaction of the RSH with the starved ribosomal complex-the ultimate inducer of (p)ppGpp production by RelA and Rel-and, second, that the hydrolytic activity of Rel is not abrogated in the truncated mutant. Therefore, we conclude that the overproduction of (p)ppGpp by RSHs lacking the RRM domain is not explained by a lack of auto-inhibition in the absence of RRM or/and a defect in (p)ppGpp hydrolysis. Instead, we argue that it is driven by misregulation of the RSH activation by the ribosome.

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Section: Introductionmentioning

confidence: 99%

The C-Terminal RRM/ACT Domain Is Crucial for Fine-Tuning the Activation of ‘Long’ RelA-SpoT Homolog Enzymes by Ribosomal Complexes

et al. 2020

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“…The intracellular concentration of the (p)ppGpp alarmone is regulated by RelA/SpoT Homologue (RSH) enzymes, which synthesise (p)ppGpp from ATP (Adenosine triphosphate) and GTP (Guanosine-5 -triphosphate)/GDP (Guanosine diphosphate) and hydrolyze (p)ppGpp to GTP/GDP and pyrophosphate, respectively. Unlike RelA, which has only synthetic activity stimulated by amino acid deprivation, SpoT is a bifunctional enzyme with both (p)ppGpp synthetic and hydrolytic activities acting as a signaling hub protein that senses and modulates responses to multiple nutritional stresses other than amino acid starvation such as fatty acid, carbon, iron, and phosphate-depleted environments [59][60][61]. Amino acid starvation leads to increased levels of deacylated tRNAs in the cytosol.…”

Section: The Stringent Responsementioning

confidence: 99%

“…The main model underlying the genetic basis of persister formation involves the expression of toxin-antitoxin (TA) modules. The main role of TA systems is to regulate growth arrest and transition to the persistent state [60,[62][63][64][65]67]. TA systems consist of a pair of genes within an operon.…”

Section: Persister Cellsmentioning

confidence: 99%

Recent Advances in Surface Nanoengineering for Biofilm Prevention and Control. Part I: Molecular Basis of Biofilm Recalcitrance. Passive Anti-Biofouling Nanocoatings

Balaure

Grumezescu

2020

Nanomaterials

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Medical device-associated infections are becoming a leading cause of morbidity and mortality worldwide, prompting researchers to find new, more effective ways to control the bacterial colonisation of surfaces and biofilm development. Bacteria in biofilms exhibit a set of “emergent properties”, meaning those properties that are not predictable from the study of free-living bacterial cells. The social coordinated behaviour in the biofilm lifestyle involves intricate signaling pathways and molecular mechanisms underlying the gain in resistance and tolerance (recalcitrance) towards antimicrobial agents as compared to free-floating bacteria. Nanotechnology provides powerful tools to disrupt the processes responsible for recalcitrance development in all stages of the biofilm life cycle. The present paper is a state-of-the-art review of the surface nanoengineering strategies currently used to design antibiofilm coatings. The review is structurally organised in two parts according to the targeted biofilm life cycle stages and molecular mechanisms intervening in recalcitrance development. Therefore, in the present first part, we begin with a presentation of the current knowledge of the molecular mechanisms responsible for increased recalcitrance that have to be disrupted. Further, we deal with passive surface nanoengineering strategies that aim to prevent bacterial cells from settling onto a biotic or abiotic surface. Both “fouling-resistant” and “fouling release” strategies are addressed as well as their synergic combination in a single unique nanoplatform.

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“…However, most of the structures determined so far are in complexes with substrate analogs as these complexes explain the catalytic mechanism. A brief structural review on (p)ppGpp synthetase proteins has been described previously (Kushwaha et al, 2019b) hence current study focus only on (p)ppGpp and (p)ppGpp synthetase complexes. There are three structures of (p)ppGpp synthetases available in the Protein Data Bank in complex with (p)ppGpp.…”

Section: (P)ppgpp Synthetasementioning

confidence: 99%

“…Later on, several enzymes from various pathways were identified which are regulated by binding of (p)ppGpp nucleotides. Most of those proteins are part of the core process of molecular machinery such as replication, transcription, translation, and cellular metabolism ( Rojas et al, 1984 ; Wang et al, 2007 , 2019 ; Srivatsan and Wang, 2008 ; Kriel et al, 2012 ; Bærentsen et al, 2019 ; Kushwaha et al, 2019b ). The resultant effects of (p)ppGpp mediated regulation has been shown in virulence, host invasion, biofilm formation, persistence, long term survival, pathogenesis, antibiotic resistance, and antibiotic tolerance ( Primm et al, 2000 ; Abranches et al, 2009 ; Dalebroux et al, 2010 ; Kudrin et al, 2017 ; Prusa et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Structural Analysis of (p)ppGpp Reveals Its Versatile Binding Pattern for Diverse Types of Target Proteins

2020

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Stringent response protein as a potential target to intervene persistent bacterial infection

Cited by 29 publications

References 98 publications

The C-Terminal RRM/ACT Domain Is Crucial for Fine-Tuning the Activation of ‘Long’ RelA-SpoT Homolog Enzymes by Ribosomal Complexes

The C-Terminal RRM/ACT Domain Is Crucial for Fine-Tuning the Activation of ‘Long’ RelA-SpoT Homolog Enzymes by Ribosomal Complexes

Recent Advances in Surface Nanoengineering for Biofilm Prevention and Control. Part I: Molecular Basis of Biofilm Recalcitrance. Passive Anti-Biofouling Nanocoatings

Structural Analysis of (p)ppGpp Reveals Its Versatile Binding Pattern for Diverse Types of Target Proteins

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