Survival of the Fittest: The Relationship of (p)ppGpp With Bacterial Virulence

Kundra, Shivani; Colomer-Winter, Cristina; Lemos, José A.

doi:10.3389/fmicb.2020.601417

Cited by 30 publications

(21 citation statements)

References 134 publications

(208 reference statements)

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“…These observations are consistent with the hypothesis that RelA is, indeed, the sole source of the alarmone in this bacterium. Furthermore, consistent with the key role of (p)ppGpp-mediated signalling in bacterial virulence and antibiotic tolerance 16,17 , the likely ppGpp 0 A. baumannii DrelA strain displays increased sensitivity to multiple antibiotics 14,15 , decreased virulence in a Galleria mellonella wax moth model and deficiency in switching from the virulent opaque colony variant to the avirulent translucent colony variant 15 .…”

Section: Introductionmentioning

confidence: 58%

The structure of SpoT reveals evolutionary tuning of enzymatic output through constraint of the conformational landscape

Tamman

Ernits

Roghanian

et al. 2022

Preprint

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Stringent factors orchestrate bacterial cell reprogramming through increasing the level of the alarmones (p)ppGpp. In Beta- and Gammaproteobacteria, SpoT hydrolyses (p)ppGpp to counteract the synthetase activity of RelA. However, structural information about how SpoT controls the levels of (p)ppGpp is missing. Here we present the crystal structure of the hydrolase-only SpoT from Acinetobacter baumannii and uncover the mechanism of intra-molecular regulation of “long”-RSH factors. In contrast to ribosome-associated Rel/RelA that adopt an elongated structure, SpoT assumes a compact τ-shaped structure in which the regulatory domains wrap around a Core subdomain that controls the conformational state of the enzyme. The Core is key to the specialisation of long-RSHs towards either synthesis or hydrolysis: while the short and structured Core of SpoT stabilises the τ-state priming the HD domain for (p)ppGpp hydrolysis, the longer, more dynamic Core of RelA destabilises the τ-state precluding (p)ppGpp hydrolysis and priming RelA for synthesis

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Section: Introductionmentioning

confidence: 58%

The structure of SpoT reveals evolutionary tuning of enzymatic output through constraint of the conformational landscape

Tamman

Ernits

Roghanian

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…relA , a global regulator gene, and related homologues, modulate the expression of (p) ppG, an alarmone that regulates the expression of multiple genes involved in survival of bacteria in unfavorable environments. It is implicated in playing a role in virulence in multiple lineages of bacteria, including mycobacteria (reviewed in [ 61 ]). A single copy of a relA Mbv homologue, relA Mtb , is encoded in all mycobacterial pathogens.…”

Section: Discussionmentioning

confidence: 99%

Advances in Understanding of the Immune Response to Mycobacterial Pathogens and Vaccines through Use of Cattle and Mycobacterium avium subsp. paratuberculosis as a Prototypic Mycobacterial Pathogen

et al. 2021

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Lack of understanding of the immune response to mycobacterial pathogens has impeded progress in development of vaccines. Infection leads to development of an immune response that controls infection but is unable to eliminate the pathogen, resulting in a persistent infection. Although this puzzle remains to be solved, progress has been made using cattle as a model species to study the immune response to a prototypic mycobacterium, Mycobacterium a. paratuberculosis (Map). As chronicled in the review, incremental advances in characterizing the immune response to mycobacteria during the last 30 years with increases in information on the evolution of mycobacteria and relA, a gene regulating the stringent response, have brought us closer to an answer. We provide a brief overview of how mycobacterial pathogens were introduced into cattle during the transition of humankind to nomadic pastoralists who domesticated animals for food and farming. We summarize what is known about speciation of mycobacteria since the discovery of Mybacterium tuberculsis Mtb, M. bovis Mbv, and Map as zoonotic pathogens and discuss the challenges inherent in the development of vaccines to mycobacteria. We then describe how cattle were used to characterize the immune response to a prototypic mycobacterial pathogen and development of novel candidate vaccines.

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“…Peptidomimetics that target the (p)ppGpp-mediated stringent response could be promising anti-virulence drugs to cope with biofilm-associated infections. The stringent response appears to be involved in biofilm development, a rise in persistence, abscess formation, and host-environment adaptation ( Alford et al, 2019 ; Kundra et al, 2020 ). Although biofilms and abscesses are physiologically different, both are high-density bacterial infections that tend to be recalcitrant to antibiotic therapy ( Mansour et al, 2016 ; Pletzer et al, 2018 ).…”

Section: Biofilm Disruption By Peptidomimeticsmentioning

confidence: 99%

Peptidomimetics as Potential Anti-Virulence Drugs Against Resistant Bacterial Pathogens

2022

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The uncontrollable spread of superbugs calls for new approaches in dealing with microbial-antibiotic resistance. Accordingly, the anti-virulence approach has arisen as an attractive unconventional strategy to face multidrug-resistant pathogens. As an emergent strategy, there is an imperative demand for discovery, design, and development of anti-virulence drugs. In this regard, peptidomimetic compounds could be a valuable source of anti-virulence drugs, since these molecules circumvent several shortcomings of natural peptide-based drugs like proteolytic instability, immunogenicity, toxicity, and low bioavailability. Some emerging evidence points to the feasibility of peptidomimetics to impair pathogen virulence. Consequently, in this review, we shed some light on the potential of peptidomimetics as anti-virulence drugs to overcome antibiotic resistance. Specifically, we address the anti-virulence activity of peptidomimetics against pathogens’ secretion systems, biofilms, and quorum-sensing systems.

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Survival of the Fittest: The Relationship of (p)ppGpp With Bacterial Virulence

Cited by 30 publications

References 134 publications

The structure of SpoT reveals evolutionary tuning of enzymatic output through constraint of the conformational landscape

The structure of SpoT reveals evolutionary tuning of enzymatic output through constraint of the conformational landscape

Advances in Understanding of the Immune Response to Mycobacterial Pathogens and Vaccines through Use of Cattle and Mycobacterium avium subsp. paratuberculosis as a Prototypic Mycobacterial Pathogen

Peptidomimetics as Potential Anti-Virulence Drugs Against Resistant Bacterial Pathogens

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