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Discovery of potential anti-infectives against Staphylococcus aureus using a Caenorhabditis elegans infection model.

ABSTRACT: BACKGROUND: The limited antibiotic options for effective control of methicillin-resistant Staphylococcus aureus infections has led to calls for new therapeutic approaches to combat this human pathogen. An alternative approach to control MRSA is through the use of anti-infective agents that selectively disrupt virulence-mediated pathways without affecting microbial cell viability or by modulating the host natural immune defenses to combat the pathogen. METHODS: We established a C. elegans - S. aureus liquid-based assay to screen for potential anti-infectives against S. aureus. The assay was utilized to screen 37 natural extracts and 29 synthetic compounds for the ability to extend the lifespan of infected nematodes. Disc diffusion and MIC microdilution tests were used to evaluate the anti-microbial properties of these natural extracts and synthetic compounds whilst in vivo bacterial CFU within the C. elegans gut were also enumerated. RESULTS: We screened a total of 37 natural extracts and 29 synthetic compounds for anti-infective properties. The screen successfully revealed 14 natural extracts from six plants (Nypa fruticans, Swietenia macrophylla, Curcuma longa, Eurycoma longifolia, Orthosiphon stamineus and Silybum eburneum) and one marine sample (Faunus ater) that improved the survival of S. aureus-infected worms by at least 2.8-fold as well as 14 synthetic compounds that prolonged the survival of S. aureus-infected nematodes by 4-fold or greater. An anti-microbial screen of all positive hits demonstrated that 8/28 hits had no effect on S. aureus growth. Of these 8 candidates, 5 of them also protected the worms from MRSA infection. We also noted that worms exposed to N. fruticans root and O. stamineus leaf extracts showed reduced intestinal colonization by live S. aureus. This suggests that these extracts could possibly activate host immunity to eliminate the bacteria or interfere with factor/s that prevents pathogen accumulation. CONCLUSION: We have successfully demonstrated the utility of this liquid-based screen to identify anti-infective substances that prolong S. aureus-infected host survival without affecting bacterial cell viability.

SUBMITTER: Kong C

PROVIDER: S-EPMC3893568 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Discovery of potential anti-infectives against Staphylococcus aureus using a Caenorhabditis elegans infection model.

Kong Cin C Yehye Wageeh A WA Abd Rahman Noorsaadah N Tan Man-Wah MW Nathan Sheila S

BMC complementary and alternative medicine 20140106

<h4>Background</h4>The limited antibiotic options for effective control of methicillin-resistant Staphylococcus aureus infections has led to calls for new therapeutic approaches to combat this human pathogen. An alternative approach to control MRSA is through the use of anti-infective agents that selectively disrupt virulence-mediated pathways without affecting microbial cell viability or by modulating the host natural immune defenses to combat the pathogen.<h4>Methods</h4>We established a C. el ...[more]

PMID: 24393217

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Project description:Glycosylation is one of the most prevalent post-translational modifications in biological systems. In Caenorhabditis elegans, O-GlcNAcylation has been shown to be actively involved in the regulation of dauer formation and detoxification of toxins secreted by invading pathogens. On this backdrop, the present study is focused on understanding the role of O-GlcNAcylation in C. elegans during Staphylococcus aureus infection using a gel based proteomic approach. Results of time course killing assays with wild-type and mutants of glycosylation and comparison of results revealed an increase in the survival of the C. elegans oga-1 mutant when compared to wild-type N2 and the ogt-1 mutant. Increased survival of C. elegans N2 upon S. aureus infection in the presence of O-(2-acetamido-2-deoxy-d-glucopyranosylidenamino) N-phenylcarbamate (PUGNAc-an OGA inhibitor) further confirmed the involvement of O-GlcNAcylation in protecting C. elegans from infection. The two-dimensional gel-based proteomic analysis of the control and S. aureus infected C. elegans oga-1 mutant followed by mass spectrometric identification of differentially expressed proteins has been carried out. The results revealed that key proteins involved in ubiquitination such as Cullin-1 (CUL-1), Cullin-3 (CUL-3), BTB and MATH domain-containing protein 15 (BATH-15), ubiquitin-conjugating enzyme E2 variant 3 (UEV-3) and probable ubiquitin-conjugating enzyme E2 7 (UBC-7) are upregulated. Real-time PCR analysis further confirms the upregulation of genes encoding the above-mentioned proteins which are involved in the ubiquitin-mediated pathways in C. elegans. In addition, treatment of C. elegans wild-type N2 and the oga-1 mutant with PUGNAc + suramin and suramin (an ubiquitination inhibitor), respectively has resulted in increased sensitivity to S. aureus infection. Hence, it is presumed that upregulation of proteins involved in the ubiquitination pathway could be the key regulatory mechanism responsible for the enhanced survival of the oga-1 mutant during S. aureus infection.

Dataset Information

Discovery of potential anti-infectives against Staphylococcus aureus using a Caenorhabditis elegans infection model.

Publications

Discovery of potential anti-infectives against Staphylococcus aureus using a Caenorhabditis elegans infection model.

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