title: Targeting Bacterial Cell Wall Peptidoglycan Synthesis by Inhibition of Glycosyltransferase Activity.
abstract: Synthesis of bacterial cell wall peptidoglycan requires glycosyltransferase enzymes that transfer the disaccharide-peptide from lipid II onto the growing glycan chain. The polymerization of the glycan chain precedes cross-linking by penicillin-binding proteins and is essential for growth for key bacterial pathogens. As such, bacterial cell wall glycosyltransferases are an attractive target for antibiotic drug discovery. However, significant challenges to the development of inhibitors for these targets include the development of suitable assays and chemical matter that is suited to the nature of the binding site. We developed glycosyltransferase enzymatic activity and binding assays using the natural products moenomycin and vancomycin as model inhibitors. In addition, we designed a library of disaccharide compounds based on the minimum moenomycin fragment with peptidoglycan glycosyltransferase inhibitory activity and based on a more drug-like and synthetically versatile disaccharide building block. A subset of these disaccharide compounds bound and inhibited the glycosyltransferase enzymes, and these compounds could serve as chemical entry points for antibiotic development.
authors.affiliation: Cubist Pharmaceuticals, a wholly-owned subsidiary of Merck & Co. Inc., 65 Hayden Avenue, Lexington, MA, 02421, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Mesleh
authors.affiliation: Alchemia Limited, 3 Hi-Tech Court, Eight Mile Plains, Brisbane Technology Park, Qld, 4113, Australia.
authors.forename: Premraj
authors.initials: P
authors.lastname: Rajaratnam
authors.affiliation: Cubist Pharmaceuticals, a wholly-owned subsidiary of Merck & Co. Inc., 65 Hayden Avenue, Lexington, MA, 02421, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Conrad
authors.affiliation: Cubist Pharmaceuticals, a wholly-owned subsidiary of Merck & Co. Inc., 65 Hayden Avenue, Lexington, MA, 02421, USA.
authors.forename: Vasu
authors.initials: V
authors.lastname: Chandrasekaran
authors.affiliation: Cubist Pharmaceuticals, a wholly-owned subsidiary of Merck & Co. Inc., 65 Hayden Avenue, Lexington, MA, 02421, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Liu
authors.affiliation: Cubist Pharmaceuticals, a wholly-owned subsidiary of Merck & Co. Inc., 65 Hayden Avenue, Lexington, MA, 02421, USA.
authors.forename: Bhaumik A
authors.initials: BA
authors.lastname: Pandya
authors.affiliation: Cubist Pharmaceuticals, a wholly-owned subsidiary of Merck & Co. Inc., 65 Hayden Avenue, Lexington, MA, 02421, USA.
authors.forename: You Seok
authors.initials: YS
authors.lastname: Hwang
authors.affiliation: Agilent Technologies, Inc., 11 Audubon Road, Wakefield, MA, 01880, USA.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Rye
authors.affiliation: Alchemia Limited, 3 Hi-Tech Court, Eight Mile Plains, Brisbane Technology Park, Qld, 4113, Australia.
authors.forename: Craig
authors.initials: C
authors.lastname: Muldoon
authors.affiliation: Alchemia Limited, 3 Hi-Tech Court, Eight Mile Plains, Brisbane Technology Park, Qld, 4113, Australia.
authors.forename: Bernd
authors.initials: B
authors.lastname: Becker
authors.affiliation: Alchemia Limited, 3 Hi-Tech Court, Eight Mile Plains, Brisbane Technology Park, Qld, 4113, Australia.
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuegg
authors.affiliation: Alchemia Limited, 3 Hi-Tech Court, Eight Mile Plains, Brisbane Technology Park, Qld, 4113, Australia.
authors.forename: Wim
authors.initials: W
authors.lastname: Meutermans
authors.affiliation: Cubist Pharmaceuticals, a wholly-owned subsidiary of Merck & Co. Inc., 65 Hayden Avenue, Lexington, MA, 02421, USA.
authors.forename: Terence I
authors.initials: TI
authors.lastname: Moy
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D002473:Cell Wall / Q000378:metabolism*; D015195:Drug Design; D004926:Escherichia coli / Q000201:enzymology; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D062105:Molecular Docking Simulation; D009844:Oligosaccharides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D046915:Penicillin-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D010457:Peptidoglycan / Q000096:biosynthesis*; D046928:Peptidoglycan Glycosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013211:Staphylococcus aureus / Q000187:drug effects; D014640:Vancomycin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D009844:Oligosaccharides; D046915:Penicillin-Binding Proteins; D010457:Peptidoglycan; D014640:Vancomycin; D046928:Peptidoglycan Glycosyltransferase; C419802:moenomycin
keywords: NMR spectroscopy; drug discovery; glycosyltransferase; penicillin-binding protein; transglycosylase