title: Structure based design of an in vivo active hydroxamic acid inhibitor of P. aeruginosa LpxC.
abstract: Lipid A is an essential component of the Gram negative outer membrane, which protects the bacterium from attack of many antibiotics. The Lipid A biosynthesis pathway is essential for Gram negative bacterial growth and is unique to these bacteria. The first committed step in Lipid A biosynthesis is catalysis by LpxC, a zinc dependent deacetylase. We show the design of an LpxC inhibitor utilizing a robust model which directed efficient design of picomolar inhibitors. Analysis of physiochemical properties drove design to focus on an optimal lipophilicity profile. Further structure based design took advantage of a conserved water network over the active site, and with the optimal lipophilicity profile, led to an improved LpxC inhibitor with in vivo activity against wild type Pseudomonas aeruginosa.
authors.affiliation: Department of Chemistry, Pfizer Global Research and Development, Ann Arbor, MI 48105, USA. Joseph.Warmus@Pfizer.com
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Warmus
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Quinn
authors.forename: Clarke
authors.initials: C
authors.lastname: Taylor
authors.forename: Sean T
authors.initials: ST
authors.lastname: Murphy
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Johnson
authors.forename: Chris
authors.initials: C
authors.lastname: Limberakis
authors.forename: Daniel
authors.initials: D
authors.lastname: Ortwine
authors.forename: Joel
authors.initials: J
authors.lastname: Bronstein
authors.forename: Paul
authors.initials: P
authors.lastname: Pagano
authors.forename: John D
authors.initials: JD
authors.lastname: Knafels
authors.forename: Sandra
authors.initials: S
authors.lastname: Lightle
authors.forename: Igor
authors.initials: I
authors.lastname: Mochalkin
authors.forename: Roger
authors.initials: R
authors.lastname: Brideau
authors.forename: Terry
authors.initials: T
authors.lastname: Podoll
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D020134:Catalytic Domain; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D057927:Hydrophobic and Hydrophilic Interactions; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D008050:Lipid A / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D011485:Protein Binding; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000201:enzymology; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D008050:Lipid A; D014867:Water; D000581:Amidohydrolases; C514484:LpxC deacetylase, Pseudomonas