1. Structure based design of an in vivo active hydroxamic acid inhibitor of P. aeruginosa LpxC
- Author
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John D. Knafels, Chris Limberakis, Paul J. Pagano, Murphy Sean T, Joseph S. Warmus, Sandra Lightle, Daniel F. Ortwine, Joel C. Bronstein, Terry Podoll, Clarke Taylor, Igor Mochalkin, Johnson Timothy Allan, Cheryl L. Quinn, and Roger J. Brideau
- Subjects
Models, Molecular ,Clinical Biochemistry ,Pharmaceutical Science ,Microbial Sensitivity Tests ,Hydroxamic Acids ,medicine.disease_cause ,Biochemistry ,Amidohydrolases ,Lipid A ,Structure-Activity Relationship ,chemistry.chemical_compound ,Catalytic Domain ,Drug Discovery ,medicine ,Enzyme Inhibitors ,Molecular Biology ,Hydroxamic acid ,biology ,Pseudomonas aeruginosa ,Organic Chemistry ,Water ,Active site ,biology.organism_classification ,Anti-Bacterial Agents ,chemistry ,Lipophilic efficiency ,Drug Design ,Lipophilicity ,biology.protein ,Molecular Medicine ,Bacterial outer membrane ,Hydrophobic and Hydrophilic Interactions ,Bacteria ,Protein Binding - 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.
- Published
- 2012