title: Metronidazole-triazole conjugates: activity against Clostridium difficile and parasites.
abstract: Metronidazole has been used clinically for over 50 years as an antiparasitic and broad-spectrum antibacterial agent effective against anaerobic bacteria. However resistance to metronidazole in parasites and bacteria has been reported, and improved second-generation metronidazole analogues are needed. The copper catalysed Huigsen azide-alkyne 1,3-dipolar cycloaddition offers a way to efficiently assemble new libraries of metronidazole analogues. Several new metronidazole-triazole conjugates (Mtz-triazoles) have been identified with excellent broad spectrum antimicrobial and antiparasitic activity targeting Clostridium difficile, Entamoeba histolytica and Giardia lamblia. Cross resistance to metronidazole was observed against stable metronidazole resistant C. difficile and G. lamblia strains. However for the most potent Mtz-triazoles, the activity remained in a therapeutically relevant window.
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia.
authors.forename: Angie M
authors.initials: AM
authors.lastname: Jarrad
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia.
authors.forename: Tomislav
authors.initials: T
authors.lastname: Karoli
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, 92093, USA.
authors.forename: Anjan
authors.initials: A
authors.lastname: Debnath
authors.affiliation: Marshall Centre for Infectious Diseases Research and Training, University of Western Australia, Perth, Western Australia, 6099, Australia.
authors.forename: Chin Yen
authors.initials: CY
authors.lastname: Tay
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia.
authors.forename: Johnny X
authors.initials: JX
authors.lastname: Huang
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Kaeslin
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia.
authors.forename: Alysha G
authors.initials: AG
authors.lastname: Elliott
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Miyamoto
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia.
authors.forename: Soumya
authors.initials: S
authors.lastname: Ramu
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Kavanagh
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia.
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuegg
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.
authors.forename: Lars
authors.initials: L
authors.lastname: Eckmann
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia.
authors.forename: Mark A T
authors.initials: MA
authors.lastname: Blaskovich
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia. Electronic address: m.cooper@uq.edu.au.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Cooper
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000977:Antiparasitic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D016360:Clostridioides difficile / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004748:Entamoeba histolytica / Q000187:drug effects; D016829:Giardia lamblia / Q000187:drug effects; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008795:Metronidazole / Q000737:chemistry* / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010271:Parasites / Q000187:drug effects*; D021261:Parasitic Sensitivity Tests; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D000977:Antiparasitic Agents; D014230:Triazoles; D008795:Metronidazole
keywords: Anaerobe; Antibiotic; Click chemistry; Nitroimidazole