The Antibiotic Novobiocin Binds and Activates the ATPase That Powers Lipopolysaccharide Transport

• DOI: 10.1021/jacs.7b07736
• Publication Date: 2017-11-14T21:35:57Z
• Authors: Janine M. May; Tristan W. Owens; Michael D. Mandler; Brent W. Simpson; Michael B. Lazarus; David J. Sherman; Rebecca M. Davis; Suguru Okuda; Walter Massefski; Natividad Ruiz; Daniel Kahne
• Keywords: Novobiocin; Walker motifs; Membrane permeability

Novobiocin is an orally active antibiotic that inhibits DNA gyrase by binding the ATP-binding site in ATPase subunit. Although effective against Gram-positive pathogens, novobiocin has limited activity Gram-negative organisms due to presence of lipopolysaccharide-containing outer membrane, which acts as a permeability barrier. Using novobiocin-sensitive Escherichia coli strain with leaky we identified mutant increased resistance novobiocin. Unexpectedly, mutation increases was not found alter gyrase, but powers lipopolysaccharide (LPS) transport. Co-crystal structures, biochemical, and genetic evidence show directly binds this ATPase. does bind ATP rather interface between subunits transmembrane LPS transporter. This interaction transporter, turn alters membrane. We propose will be useful tool for understanding how hydrolysis coupled