Suppression of
            <i>Staphylococcus aureus</i>
            virulence by a small-molecule compound

Gao, Peng; Ho, Pak-Leung; Yan, Bingpeng; Sze, Kong Hung; Davies, Julian; Kao, Richard Yi Tsun

doi:10.1073/pnas.1720520115

Cited by 54 publications

(51 citation statements)

References 41 publications

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“…A growing number of studies highlight the therapeutic potential of targeting ClpP. A recent study describes a selective, small-molecule inhibitor of ClpP, identified via high-throughput screening and which attenuates virulence in mouse models of S. aureus USA300 infection (55). Our work and others suggest therapeutically targeting ClpP may have great promise in treating invasive S. aureus infections.…”

Section: Discussionmentioning

confidence: 99%

A Genome-Wide Screen Identifies Factors Involved in S. aureus-Induced Human Neutrophil Cell Death and Pathogenesis

Yang

Cowell

et al. 2019

Front. Immunol.

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Staphylococcus aureus is a commensal organism in approximately 30% of the human population and colonization is a significant risk factor for invasive infection. As a result of this, there is a great need to better understand how S. aureus overcomes human immunity. Neutrophils are essential during the innate immune response to S. aureus, yet this microorganism uses multiple evasion strategies to avoid killing by these immune cells, perhaps the most catastrophic of which is the rapid induction of neutrophil cell death. The aim of this study was to better understand the mechanisms underpinning S. aureus-induced neutrophil lysis, and how this contributes to pathogenesis in a whole organism model of infection. To do this we screened the genome-wide Nebraska Transposon Mutant Library (NTML) in the community acquired methicillin resistant S. aureus strain, USA300, for decreased ability to induce neutrophil cell lysis. Out of 1,920 S. aureus mutants, a number of known regulators of cell lysis (including the master regulators accessory gene regulator A, agrA and Staphylococcus exoprotein expression protein S, saeS) were identified in this blinded screen, providing validity to the experimental system. Three gene mutations not previously associated with cell death: purB, lspA, and clpP were found to be significantly attenuated in their ability to induce neutrophil lysis. These phenotypes were verified by genetic transductants and complemented strains. purB and clpP were subsequently found to be necessary for bacterial replication and pathogenesis in a zebrafish embryo infection model. The virulence of the clpP mutant was restored in a neutrophil-depleted zebrafish model, suggesting the importance of ClpP in mechanisms underpinning neutrophil immunity to S. aureus. In conclusion, our work identifies genetic components underpinning S. aureus pathogenesis, and may provide insight into how this commensal organism breaches innate immune barriers during infection.

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Section: Discussionmentioning

confidence: 99%

A Genome-Wide Screen Identifies Factors Involved in S. aureus-Induced Human Neutrophil Cell Death and Pathogenesis

Yang

Cowell

et al. 2019

Front. Immunol.

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“…aureus UAMS-1 [59], it is possible that CodY negatively regulates urease gene transcription through repressing Agr, since the agrA gene encoding the Agr response regulator is upregulated in the UAMS-1 ΔcodY mutant [59]. More in-depth future studies are required regarding the regulation of urease, as other transcriptional regulators such as Sae [60, 61], ClpP [62–64], and MgrA [65], are suggested to contribute to the regulatory network that fine-tunes urease activity. Lastly, it is interesting that CcpA activates ure transcription but represses rocF (arginase) transcription.…”

Section: Discussionmentioning

confidence: 99%

Urease is an essential component of the acid response network of Staphylococcus aureus and is required for a persistent murine kidney infection

et al. 2019

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Staphylococcus aureus causes acute and chronic infections resulting in significant morbidity. Urease, an enzyme that generates NH3 and CO2 from urea, is key to pH homeostasis in bacterial pathogens under acidic stress and nitrogen limitation. However, the function of urease in S. aureus niche colonization and nitrogen metabolism has not been extensively studied. We discovered that urease is essential for pH homeostasis and viability in urea-rich environments under weak acid stress. The regulation of urease transcription by CcpA, Agr, and CodY was identified in this study, implying a complex network that controls urease expression in response to changes in metabolic flux. In addition, it was determined that the endogenous urea derived from arginine is not a significant contributor to the intracellular nitrogen pool in non-acidic conditions. Furthermore, we found that during a murine chronic renal infection, urease facilitates S. aureus persistence by promoting bacterial fitness in the low-pH, urea-rich kidney. Overall, our study establishes that urease in S. aureus is not only a primary component of the acid response network but also an important factor required for persistent murine renal infections.

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“…Within this complex, ClpX 6 recognizes and unfolds substrate proteins for subsequent digestion by ClpP 14 . Previous research identified various small‐molecule inhibitors of ClpP . Among those, reversible oxazole compounds displayed excellent potency on the ClpP peptidase but suffered from a ClpX‐mediated repulsion based on conformational selection, thus preventing inhibition of ClpXP .…”

Section: Figurementioning

confidence: 99%

Tailored Peptide Phenyl Esters Block ClpXP Proteolysis by an Unusual Breakdown into a Heptamer–Hexamer Assembly

et al. 2019

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The proteolytic complex ClpXP is fundamental to bacterial homeostasis and pathogenesis.B ecause of its conformational flexibility,t he development of potent ClpXP inhibitors is challenging,a nd novel tools to decipher its intricate regulation are urgently needed. Herein, we present amino acid based phenyl esters as molecular probes to study the activity and oligomerization of the ClpXP complex of S. aureus.Systematic screening of (R)-and (S)-amino acids led to compounds showing potent inhibition, as well as stimulation of ClpXP-mediated proteolysis.S ubstoichiometric binding of probes arrested ClpXP in an unprecedented heptamer-hexamer assembly,i nw hicht he two heptameric ClpP rings are dissociated from eacho ther.A tt he same time,t he affinity between ClpX and ClpP increased, leading to inhibition of both enzymes.T his conformational arrest is beneficial for the consolidated shutdown of ClpXP,aswell as for the study of the oligomeric state during its catalytic cycle.

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Suppression of Staphylococcus aureus virulence by a small-molecule compound

Cited by 54 publications

References 41 publications

A Genome-Wide Screen Identifies Factors Involved in S. aureus-Induced Human Neutrophil Cell Death and Pathogenesis

A Genome-Wide Screen Identifies Factors Involved in S. aureus-Induced Human Neutrophil Cell Death and Pathogenesis

Urease is an essential component of the acid response network of Staphylococcus aureus and is required for a persistent murine kidney infection

Tailored Peptide Phenyl Esters Block ClpXP Proteolysis by an Unusual Breakdown into a Heptamer–Hexamer Assembly

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