An update on the use of C. elegans for preclinical drug discovery: screening and identifying anti-infective drugs

ABSTRACT

Introduction: The emergence of antibiotic-resistant and -tolerant bacteria is a major threat to human health. Although efforts for drug discovery are ongoing, conventional bacteria-centered screening strategies have thus far failed to yield new classes of effective antibiotics. Therefore, new paradigms for discovering novel antibiotics are of critical importance. Caenorhabditis elegans, a model organism used for in vivo, offers a promising solution for identification of anti-infective compounds.

Areas covered: This review examines the advantages of C. elegans-based high-throughput screening over conventional, bacteria-centered in vitro screens. It discusses major anti-infective compounds identified from large-scale C. elegans-based screens and presents the first clinically-approved drugs, then known bioactive compounds, and finally novel small molecules.

Expert opinion: There are clear advantages of using a C. elegans-infection based screening method. A C. elegans-based screen produces an enriched pool of non-toxic, efficacious, potential anti-infectives, covering: conventional antimicrobial agents, immunomodulators, and anti-virulence agents. Although C. elegans-based screens do not denote the mode of action of hit compounds, this can be elucidated in secondary studies by comparing the results to target-based screens, or conducting subsequent target-based screens, including the genetic knock-down of host or bacterial genes.

KEYWORDS:

• Caenorhabditis elegans
• drug discovery
• high-throughput screen
• antibiotics

Article highlights

• C. elegans-based in vivo screening strategies provide expanded identification of anti-infectives from conventional antibiotics to anti-virulence agents and immunomodulators.

• C. elegans-based screens simultaneously exclude large number of non-efficacious or toxic compounds commonly identified in conventional, target-based screens.

• C. elegans-based screens satisfy up to TRL3, whereas conventional screens require additional, labor intensive and costly in vivo toxicity tests to fully satisfy TRL3.

• MOAs of hit compounds identified by C. elegans screens can be determined by comparing the hits from target-based screens or conducting subsequent target-based screens.

• C. elegans-based screens represent a paradigm shift in high-throughput screening platforms that has tremendous potential for finding the new anti-infective agents.

This box summarizes key points contained in the article.

Acknowledgments

Beth Fuchs of Brown University, USA and Heather Kolpa of Custom Learningn Designs Inc, Belmont, MA USA for their proofreading.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This study was supported by National Institutes of Health grant P01 AI083214 provided to E Mylonakis