title: Disarming Pseudomonas aeruginosa virulence factor LasB by leveraging a Caenorhabditis elegans infection model.
abstract: The emergence of antibiotic resistance places a sense of urgency on the development of alternative antibacterial strategies, of which targeting virulence factors has been regarded as a "second generation" antibiotic approach. In the case of Pseudomonas aeruginosa infections, a proteolytic virulence factor, LasB, is one such target. Unfortunately, we and others have not been successful in translating in vitro potency of LasB inhibitors to in vivo efficacy in an animal model. To overcome this obstacle, we now integrate in silico and in vitro identification of the mercaptoacetamide motif as an effective class of LasB inhibitors with full in vivo characterization of mercaptoacetamide prodrugs using Caenorhabditis elegans. We show that one of our mercaptoacetamide prodrugs has a good selectivity profile and high in vivo efficacy, and confirm that LasB is a promising target for the treatment of bacterial infections. In addition, our work highlights that the C. elegans infection model is a user-friendly and cost-effective translational tool for the development of anti-virulence compounds.
authors.affiliation: The Skaggs Institute for Chemical Biology and Departments of Chemistry and Immunology and the Worm Institute for Research and Medicine (WIRM), La Jolla, CA 92037, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhu
authors.affiliation: The Skaggs Institute for Chemical Biology and Departments of Chemistry and Immunology and the Worm Institute for Research and Medicine (WIRM), La Jolla, CA 92037, USA.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Cai
authors.affiliation: The Skaggs Institute for Chemical Biology and Departments of Chemistry and Immunology and the Worm Institute for Research and Medicine (WIRM), La Jolla, CA 92037, USA.
authors.forename: Tyler L
authors.initials: TL
authors.lastname: Harris
authors.affiliation: The Skaggs Institute for Chemical Biology and Departments of Chemistry and Immunology and the Worm Institute for Research and Medicine (WIRM), La Jolla, CA 92037, USA.
authors.forename: Major
authors.initials: M
authors.lastname: Gooyit
authors.affiliation: The Core Microscopy Facility, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Wood
authors.affiliation: Computational Chemistry, Principia Biopharma, 400 East Jamie Court, South San Francisco, CA 94080, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Lardy
authors.affiliation: The Skaggs Institute for Chemical Biology and Departments of Chemistry and Immunology and the Worm Institute for Research and Medicine (WIRM), La Jolla, CA 92037, USA. Electronic address: kdjanda@scripps.edu.
authors.forename: Kim D
authors.initials: KD
authors.lastname: Janda
mesh_terms: D000081:Acetamides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D017173:Caenorhabditis elegans / Q000382:microbiology*; D020134:Catalytic Domain; D004195:Disease Models, Animal; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D046529:Microscopy, Electron, Transmission; D062105:Molecular Docking Simulation; D011355:Prodrugs / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry; D037521:Virulence Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000081:Acetamides; D001426:Bacterial Proteins; D011355:Prodrugs; D013438:Sulfhydryl Compounds; D037521:Virulence Factors; C030686:acetamide; D008666:Metalloendopeptidases; C043859:pseudolysin, Pseudomonas aeruginosa