RNAIII‐Inhibiting Peptide Significantly Reduces Bacterial Load and Enhances the Effect of Antibiotics in the Treatment of Central Venous Catheter–Associated<i>Staphylococcus aureus</i>Infections

Cirioni, Oscar; Giacometti, Andrea; Ghiselli, Roberto; Dell'Acqua, Giorgio; Orlando, Fiorenza; Mocchegiani, Federico; Silvestri, Carmela; Licci, Alberto; Saba, Vittorio; Scalise, Giorgio; Balaban, Naomi

doi:10.1086/498914

Cited by 82 publications

(53 citation statements)

References 49 publications

(83 reference statements)

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“…RNAIII-inhibiting peptide (RIP), a compound interfering with S. aureus QS, efficiently prevents CVC-related infection in vivo, alone or in association with antibiotics, in a rat model (294). Similar in vitro and in vivo data have been published for S. epidermidis (295).…”

Section: Targeting Biofilm Recalcitrance: Progress and Perspectivesmentioning

confidence: 71%

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

Lebeaux

Ghigo

Beloin

2014

Microbiol Mol Biol Rev

961

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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Section: Targeting Biofilm Recalcitrance: Progress and Perspectivesmentioning

confidence: 71%

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

Lebeaux

Ghigo

Beloin

2014

Microbiol Mol Biol Rev

961

862

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“…Lyon et al attempted to rationally design a peptide antagonist of the agr pheromone and were successful (31,32). An RNA-III-inhibiting peptide found in culture filtrates of some staphylococcal strains is also thought to be an antistaphylococcal agent (1,4,9,13,21,63).…”

mentioning

confidence: 99%

Siamycin Attenuates fsr Quorum Sensing Mediated by a Gelatinase Biosynthesis-Activating Pheromone in Enterococcus faecalis

Nakayama¹,

Tanaka²,

Kariyama

et al. 2007

J Bacteriol

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The expression of two Enterococcus faecalis virulence-related proteases, gelatinase (GelE) and serine protease (SprE), is positively regulated by a quorum-sensing system encoded by the fsr gene cluster. In this system, E. faecalis secretes an autoinducing peptide, gelatinase biosynthesis-activating pheromone (GBAP), which triggers the FsrC-FsrA two-component regulatory system controlling the expression of two transcripts, fsrBDC and gelE-sprE. In the present study, we screened actinomycete metabolites for inhibitors of fsr quorum sensing. E. faecalis was cultured with each actinomycete culture supernatant tested, and the production of gelatinase and the production of GBAP were examined using the first screening and the second screening, respectively. Culture supernatant of Streptomyces sp. strain Y33-1 had the most potent inhibitory effect on both gelatinase production and GBAP production without inhibiting E. faecalis cell growth. The inhibitor in the culture supernatant was identified as a known peptide antibiotic, siamycin I. Siamycin I inhibited both gelatinase production and GBAP production at submicromolar concentrations, and it inhibited E. faecalis cell growth at concentrations above micromolar concentrations. Quantitative analysis of fsrBDC and gelE-sprE transcripts revealed that siamycin I suppressed the expression of both transcripts at a sublethal concentration. Siamycin I attenuated gelatinase production even when an overdose of GBAP was exogenously added to the culture. These results suggested that siamycin I inhibited the GBAP signaling via the FsrC-FsrA two-component regulatory system in a noncompetitive manner. The sublethal concentrations of siamycin I also attenuated biofilm formation. Treatment with siamycin could be a novel means of treating enterococcal infections.Enterococcus faecalis is a gram-positive intestinal commensal of humans and other animals, but it sometimes causes opportunistic infections, including urinary tract, bloodstream, and wound infections, endophtalmitis, and endocarditis (22). Notably, in the past two decades, nosocomial infections caused by multiple-antibiotic-resistant or vancomycin-resistant E. faecalis have become a serious clinical problem (6,33,36,49).Besides cytolysin, which is lethal by itself for a broad range of prokaryotic and eukaryotic cells (10), several virulence-related factors have been found in E. faecalis, including aggregation substance (Agg), enterococcal surface protein (Esp), and two extracellular proteases, gelatinase (GelE) and serine protease (SprE) (35, 59). These factors have been thought to act synergistically to enhance virulence by facilitating colonization, translocation, and biofilm formation (8,16,23,28,34,35,52,60,62,65). GelE and SprE are encoded in an operon, gelE-sprE, whose expression is positively regulated by a quorum-sensing system encoded by the fsr locus (45,46). Several in vivo studies using animal or nematode models have shown that the fsr system contributes to virulence (17,19,37,46,53).The fsr locus is comprised of four ...

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“…The traP gene reportedly encodes a response regulator (TraP) that is triply phosphorylated as a result of the accumulation of a protein designated RAP (RNAIII-activating peptide), resulting in activation of the agr regulatory system and induction of toxin synthesis (21). A number of studies have also concluded that clinical isolates of S. aureus are responsive to RAP and that a modified peptide derivative designated RIP (RNAIIIinhibiting peptide) can be used to limit phosphorylation of TraP and thereby limit induction of agr, the capacity to form a biofilm, and virulence (1,3,12,14,24).To the extent that both RAP and RIP reportedly function by modulating the activity of TraP, studies indicating that clinical isolates are responsive to RAP and RIP would suggest that the traP regulatory system functions in the same fashion in most if not all S. aureus strains. However, the primary focus to date, particularly in terms of direct mutagenesis studies, has been on derivatives of the prototype 8325-4 laboratory strain such as RN6390, and recent studies from our laboratory have confirmed that regulatory circuits in RN6390 are different than those observed in at least some clinical isolates (9, 11).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Mutation of traP in Staphylococcus aureus Has No Impact on Expression of agr or Biofilm Formation

et al. 2007

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To investigate the regulatory role of traP (target of RNAIII-activating peptide) in Staphylococcus aureus, we generated traP mutations in the clinical isolates UAMS-1 and USA300. In neither case did mutation of traP affect expression of the accessory gene regulator (agr) or the ability to form a biofilm. We were also unable to confirm that mutation of traP in the prototype 8325-4 laboratory strain RN6390 results in reduced expression of agr, reduced hemolytic activity, or an altered capacity to form a biofilm.There is a growing body of literature indicating that mutation or inhibition of the Staphylococcus aureus regulatory locus designated traP (target of RNAIII-activating peptide) results in reduced expression of the accessory gene regulator (agr), a reduced capacity to form a biofilm, and reduced virulence in animal models of staphylococcal disease (3,5,6,17,23,28). The traP gene reportedly encodes a response regulator (TraP) that is triply phosphorylated as a result of the accumulation of a protein designated RAP (RNAIII-activating peptide), resulting in activation of the agr regulatory system and induction of toxin synthesis (21). A number of studies have also concluded that clinical isolates of S. aureus are responsive to RAP and that a modified peptide derivative designated RIP (RNAIIIinhibiting peptide) can be used to limit phosphorylation of TraP and thereby limit induction of agr, the capacity to form a biofilm, and virulence (1,3,12,14,24).To the extent that both RAP and RIP reportedly function by modulating the activity of TraP, studies indicating that clinical isolates are responsive to RAP and RIP would suggest that the traP regulatory system functions in the same fashion in most if not all S. aureus strains. However, the primary focus to date, particularly in terms of direct mutagenesis studies, has been on derivatives of the prototype 8325-4 laboratory strain such as RN6390, and recent studies from our laboratory have confirmed that regulatory circuits in RN6390 are different than those observed in at least some clinical isolates (9, 11). One such difference is the impact of agr on biofilm formation. Specifically, mutation of agr enhances biofilm formation in RN6390 but has little impact in clinical isolates (7,29). Since TraP reportedly functions through an agr-dependent pathway, we wanted to investigate whether similar, strain-dependent differences also existed with respect to traP. To that end, we mutated traP in two clinical isolates (UAMS-1 and USA300-0114) as well as our version of the prototype laboratory strain RN6390. The impact of mutating traP in all three strains was assessed based on biofilm formation, hemolytic activity, and production of the agr-encoded regulatory molecule RNAIII.

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RNAIII‐Inhibiting Peptide Significantly Reduces Bacterial Load and Enhances the Effect of Antibiotics in the Treatment of Central Venous Catheter–AssociatedStaphylococcus aureusInfections

Abstract: RIP significantly reduces bacterial load and enhances the effect of antibiotics in the treatment of CVC-associated S. aureus infections.

Cited by 82 publications

References 49 publications

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

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

Siamycin Attenuates fsr Quorum Sensing Mediated by a Gelatinase Biosynthesis-Activating Pheromone in Enterococcus faecalis

Mutation of traP in Staphylococcus aureus Has No Impact on Expression of agr or Biofilm Formation

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