title: Carbohydrate scaffolds as glycosyltransferase inhibitors with in vivo antibacterial activity.
abstract: The rapid rise of multi-drug-resistant bacteria is a global healthcare crisis, and new antibiotics are urgently required, especially those with modes of action that have low-resistance potential. One promising lead is the liposaccharide antibiotic moenomycin that inhibits bacterial glycosyltransferases, which are essential for peptidoglycan polymerization, while displaying a low rate of resistance. Unfortunately, the lipophilicity of moenomycin leads to unfavourable pharmacokinetic properties that render it unsuitable for systemic administration. In this study, we show that using moenomycin and other glycosyltransferase inhibitors as templates, we were able to synthesize compound libraries based on novel pyranose scaffold chemistry, with moenomycin-like activity, but with improved drug-like properties. The novel compounds exhibit in vitro inhibition comparable to moenomycin, with low toxicity and good efficacy in several in vivo models of infection. This approach based on non-planar carbohydrate scaffolds provides a new opportunity to develop new antibiotics with low propensity for resistance induction.
authors.affiliation: 1] Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia [2] Alchemia Ltd, PO Box 4851, Eight Mile Plains, Brisbane, Queensland 4113, Australia.
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuegg
authors.affiliation: Alchemia Ltd, PO Box 4851, Eight Mile Plains, Brisbane, Queensland 4113, Australia.
authors.forename: Craig
authors.initials: C
authors.lastname: Muldoon
authors.affiliation: Alchemia Ltd, PO Box 4851, Eight Mile Plains, Brisbane, Queensland 4113, Australia.
authors.forename: George
authors.initials: G
authors.lastname: Adamson
authors.affiliation: Alchemia Ltd, PO Box 4851, Eight Mile Plains, Brisbane, Queensland 4113, Australia.
authors.forename: Declan
authors.initials: D
authors.lastname: McKeveney
authors.affiliation: Alchemia Ltd, PO Box 4851, Eight Mile Plains, Brisbane, Queensland 4113, Australia.
authors.forename: Giang
authors.initials: G
authors.lastname: Le Thanh
authors.affiliation: Alchemia Ltd, PO Box 4851, Eight Mile Plains, Brisbane, Queensland 4113, Australia.
authors.forename: Rajaratnam
authors.initials: R
authors.lastname: Premraj
authors.affiliation: Alchemia Ltd, PO Box 4851, Eight Mile Plains, Brisbane, Queensland 4113, Australia.
authors.forename: Bernd
authors.initials: B
authors.lastname: Becker
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
authors.forename: Mu
authors.initials: M
authors.lastname: Cheng
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
authors.forename: Alysha G
authors.initials: AG
authors.lastname: Elliott
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
authors.forename: Johnny X
authors.initials: JX
authors.lastname: Huang
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
authors.forename: Mark S
authors.identifier: 0000000166894236
authors.initials: MS
authors.lastname: Butler
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
authors.forename: Megha
authors.initials: M
authors.lastname: Bajaj
authors.affiliation: Alchemia Ltd, PO Box 4851, Eight Mile Plains, Brisbane, Queensland 4113, Australia.
authors.forename: Joachim
authors.initials: J
authors.lastname: Seifert
authors.affiliation: Alchemia Ltd, PO Box 4851, Eight Mile Plains, Brisbane, Queensland 4113, Australia.
authors.forename: Latika
authors.initials: L
authors.lastname: Singh
authors.affiliation: School of Life Science, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK.
authors.forename: Nicola F
authors.initials: NF
authors.lastname: Galley
authors.affiliation: School of Life Science, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK.
authors.forename: David I
authors.initials: DI
authors.lastname: Roper
authors.affiliation: School of Life Science, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK.
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Lloyd
authors.affiliation: School of Life Science, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Dowson
authors.affiliation: Genomics Research Center, Academia Sinica, 128 Academia Road, Section 2, Taipei 115, Taiwan.
authors.forename: Ting-Jen
authors.initials: TJ
authors.lastname: Cheng
authors.affiliation: Genomics Research Center, Academia Sinica, 128 Academia Road, Section 2, Taipei 115, Taiwan.
authors.forename: Wei-Chieh
authors.initials: WC
authors.lastname: Cheng
authors.affiliation: Faculty of Veterinary Medicine, Laboratory of Biochemistry, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium.
authors.forename: Dieter
authors.initials: D
authors.lastname: Demon
authors.affiliation: Faculty of Veterinary Medicine, Laboratory of Biochemistry, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Meyer
authors.affiliation: Alchemia Ltd, PO Box 4851, Eight Mile Plains, Brisbane, Queensland 4113, Australia.
authors.forename: Wim
authors.initials: W
authors.lastname: Meutermans
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Cooper
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D005260:Female; D016695:Glycosyltransferases / Q000037:antagonists & inhibitors*; D006801:Humans; D008413:Mastitis / Q000188:drug therapy; D051379:Mice; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D009844:Oligosaccharides / Q000737:chemistry*; D013211:Staphylococcus aureus
chemical_list: D000900:Anti-Bacterial Agents; D009844:Oligosaccharides; D016695:Glycosyltransferases; C419802:moenomycin