Design and synthesis of peptides from bacterial ParE toxin as inhibitors of topoisomerases

Barbosa, Luiz Carlos Bertucci; Garrido, Saulo Santesso; Garcia, Anderson; Delfino, Davi Barbosa; Santos, Laura do Nascimento; Marchetto, Reinaldo

doi:10.1016/j.ejmech.2012.06.008

Cited by 15 publications

(14 citation statements)

References 39 publications

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“…ParE toxin of ParDE TA system of E. coli blocks DNA replication by inhibiting DNA gyrase activity. Peptides designed on the basis of E. coli ParE toxin structure showed inhibition of bacterial DNA gyrase as well as topoisomerase activity (Barbosa et al, 2012). Two other peptide-based strategies have been reported in MazF family TA system.…”

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confidence: 99%

Structural basis ofBacillus anthracisMoxXT disruption and the modulation of MoxT ribonuclease activity by rationally designed peptides

Verma

Kumar

Gupta

et al. 2014

Journal of Biomolecular Structure and Dynamics

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Bacillus anthracis MoxXT is a Type II proteic Toxin-Antitoxin (TA) module wherein MoxT is a ribonuclease that cleaves RNA specifically while MoxX interacts with MoxT and inhibits its activity. Disruption of the TA interaction has been proposed as a novel antibacterial strategy. Peptides, either based on antitoxin sequence or rationally designed, have previously been reported to disrupt the MoxXT interaction but cause a decrease in MoxT ribonuclease activity. In the present study, we report the crystal structure of MoxT, and the effect of several peptides in disrupting the MoxXT interaction as well as augmentation of MoxT ribonuclease activity by binding to MoxT in vitro. Docking studies on the peptides were carried out in order to explain the observed structure activity relationships. The peptides with ribonuclease augmentation activity possess a distinct structure and are proposed to bind to a distinct site on MoxT. The docking of the active peptides with MoxT showed that they possess an aromatic group that occupies a conserved hydrophobic pocket. Additionally, the peptides inducing high ribonuclease activity were anchored by a negatively charged group near a cluster of positively charged residues present near the pocket. Our study provides a structural basis and rationale for the observed properties of the peptides and may aid the development of small molecules to disrupt the TA interaction.

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confidence: 99%

Structural basis ofBacillus anthracisMoxXT disruption and the modulation of MoxT ribonuclease activity by rationally designed peptides

Verma

Kumar

Gupta

et al. 2014

Journal of Biomolecular Structure and Dynamics

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“…A most exciting approach has been made by the finding that small synthetic peptides derived from the ParE toxin from E. coli (included as a member of the RelE toxin superfamily) as well as peptides derived from the CcdB toxin were able to inhibit topoisomerases (from bacteria to humans) in vitro, a discovery which no doubt will open new uses for the toxicity of the toxins (10,144). Whether this approach can be used to design small RNAs that encode the desired peptides and, if so, whether they can be used as potential antibacterials remain to be seen.…”

Section: Conclusion and Perspectives: Use Of Tas As Antimicrobialsmentioning

confidence: 99%

Toxin-Antitoxin Genes of the Gram-Positive Pathogen Streptococcus pneumoniae: So Few and Yet So Many

Chan

Moreno-Córdoba

Yeo

et al. 2012

Microbiol Mol Biol Rev

127

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SUMMARYPneumococcal infections cause up to 2 million deaths annually and raise a large economic burden and thus constitute an important threat to mankind. Because of the increase in the antibiotic resistance ofStreptococcus pneumoniaeclinical isolates, there is an urgent need to find new antimicrobial approaches to triumph over pneumococcal infections. Toxin-antitoxin (TA) systems (TAS), which are present in most living bacteria but not in eukaryotes, have been proposed as an effective strategy to combat bacterial infections. Type II TAS comprise a stable toxin and a labile antitoxin that form an innocuous TA complex under normal conditions. Under stress conditions, TA synthesis will be triggered, resulting in the degradation of the labile antitoxin and the release of the toxin protein, which would poison the host cells. The three functional chromosomal TAS fromS. pneumoniaethat have been studied as well as their molecular characteristics are discussed in detail in this review. Furthermore, a meticulous bioinformatics search has been performed for 48 pneumococcal genomes that are found in public databases, and more putative TAS, homologous to well-characterized ones, have been revealed. Strikingly, several unusual putative TAS, in terms of components and genetic organizations previously not envisaged, have been discovered and are further discussed. Previously, we reported a novel finding in which a unique pneumococcal DNA signature, the BOX element, affected the regulation of the pneumococcalyefM-yoeBTAS. This BOX element has also been found in some of the other pneumococcal TAS. In this review, we also discuss possible relationships between some of the pneumococcal TAS with pathogenicity, competence, biofilm formation, persistence, and an interesting phenomenon called bistability.

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“…Peptides based on the structure of the ParE toxin have been used as inhibitors of bacterial topoisomerases [130]. Analogously, the Extracellular Death Factor is an endogenous pentapeptide activator of the MazF toxin [60] which indicates the existence of natural ligands that may be exploited to moderate TA complex function.…”

Section: New Antibiotics That Interfere With Ta Transcriptional Amentioning

confidence: 99%

Regulating Toxin-Antitoxin Expression: Controlled Detonation of Intracellular Molecular Timebombs

Hayes

Kędzierska

2014

Toxins

101

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Genes for toxin-antitoxin (TA) complexes are widely disseminated in bacteria, including in pathogenic and antibiotic resistant species. The toxins are liberated from association with the cognate antitoxins by certain physiological triggers to impair vital cellular functions. TAs also are implicated in antibiotic persistence, biofilm formation, and bacteriophage resistance. Among the ever increasing number of TA modules that have been identified, the most numerous are complexes in which both toxin and antitoxin are proteins. Transcriptional autoregulation of the operons encoding these complexes is key to ensuring balanced TA production and to prevent inadvertent toxin release. Control typically is exerted by binding of the antitoxin to regulatory sequences upstream of the operons. The toxin protein commonly works as a transcriptional corepressor that remodels and stabilizes the antitoxin. However, there are notable exceptions to this paradigm. Moreover, it is becoming clear that TA complexes often form one strand in an interconnected web of stress responses suggesting that their transcriptional regulation may prove to be more intricate than currently understood. Furthermore, interference with TA gene transcriptional autoregulation holds considerable promise as a novel antibacterial strategy: artificial release of the toxin factor using designer drugs is a potential approach to induce bacterial suicide from within.

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Design and synthesis of peptides from bacterial ParE toxin as inhibitors of topoisomerases

Cited by 15 publications

References 39 publications

Structural basis ofBacillus anthracisMoxXT disruption and the modulation of MoxT ribonuclease activity by rationally designed peptides

Structural basis ofBacillus anthracisMoxXT disruption and the modulation of MoxT ribonuclease activity by rationally designed peptides

Toxin-Antitoxin Genes of the Gram-Positive Pathogen Streptococcus pneumoniae: So Few and Yet So Many

Regulating Toxin-Antitoxin Expression: Controlled Detonation of Intracellular Molecular Timebombs

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