title: Exploring the UDP pocket of LpxC through amino acid analogs.
abstract: Lipopolysaccharide (LPS) biosynthesis is an attractive antibacterial target as it is both conserved and essential for the survival of key pathogenic bacteria. Lipid A is the hydrophobic anchor for LPS and a key structural component of the outer membrane of Gram-negative bacteria. Lipid A biosynthesis is performed in part by a unique zinc dependent metalloamidase, LpxC (UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase), which catalyzes the first non-reversible step in lipid A biosynthesis. The UDP portion of the LpxC substrate-binding pocket has been relatively unexplored. We have designed and evaluated a series of hydroxamate based inhibitors which explore the SAR of substitutions directed into the UDP pocket with a range of substituted α-amino acid based linkers. We also provide the first wild type structure of Pseudomonas aeruginosa LpxC which was utilized in the design of many of these analogs.
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. michael.hale@astrazeneca.com
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hale
authors.forename: Pamela
authors.initials: P
authors.lastname: Hill
authors.forename: Sushmita
authors.initials: S
authors.lastname: Lahiri
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Miller
authors.forename: Philip
authors.initials: P
authors.lastname: Ross
authors.forename: Richard
authors.initials: R
authors.lastname: Alm
authors.forename: Ning
authors.initials: N
authors.lastname: Gao
authors.forename: Amy
authors.initials: A
authors.lastname: Kutschke
authors.forename: Michele
authors.initials: M
authors.lastname: Johnstone
authors.forename: Bryan
authors.initials: B
authors.lastname: Prince
authors.forename: Jason
authors.initials: J
authors.lastname: Thresher
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D000595:Amino Acid Sequence; D000598:Amino Acids, Cyclic / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry; D001665:Binding Sites; D015195:Drug Design; D057927:Hydrophobic and Hydrophilic Interactions; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008050:Lipid A / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008958:Models, Molecular; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014530:Uridine Diphosphate / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000598:Amino Acids, Cyclic; D000900:Anti-Bacterial Agents; D006877:Hydroxamic Acids; D008050:Lipid A; D008070:Lipopolysaccharides; D014530:Uridine Diphosphate; D000581:Amidohydrolases; C514484:LpxC deacetylase, Pseudomonas