title: 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.
  
  
  CONCLUSIONS
  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.
authors.forename: Cin
authors.initials: C
authors.lastname: Kong
authors.forename: Wageeh A
authors.initials: WA
authors.lastname: Yehye
authors.forename: Noorsaadah
authors.initials: N
authors.lastname: Abd Rahman
authors.forename: Man-Wah
authors.initials: MW
authors.lastname: Tan
authors.affiliation: School of Biosciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 UKM Bangi, Selangor, Malaysia. sheila@ukm.my.
authors.forename: Sheila
authors.initials: S
authors.lastname: Nathan
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D058491:Bacterial Load / Q000187:drug effects; D001688:Biological Products / Q000494:pharmacology / Q000627:therapeutic use; D017173:Caenorhabditis elegans / Q000382:microbiology*; D004195:Disease Models, Animal; D052978:Disk Diffusion Antimicrobial Tests; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D007422:Intestines / Q000187:drug effects / Q000382:microbiology; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000472:pathogenicity; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D010936:Plant Extracts / Q000494:pharmacology* / Q000627:therapeutic use; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000472:pathogenicity; D016019:Survival Analysis; D014774:Virulence / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D001688:Biological Products; D010936:Plant Extracts