2. Academic Validation
  3. Disrupting Gram-Negative Bacterial Outer Membrane Biosynthesis through Inhibition of the Lipopolysaccharide Transporter MsbA

Disrupting Gram-Negative Bacterial Outer Membrane Biosynthesis through Inhibition of the Lipopolysaccharide Transporter MsbA

  • Antimicrob Agents Chemother. 2018 Oct 24;62(11):e01142-18. doi: 10.1128/AAC.01142-18.
Mary Kate Alexander 1,  Anh Miu 2,  Angela Oh 3,  Mike Reichelt 4,  Hoangdung Ho 3,  Cecile Chalouni 4,  Sharada Labadie 5,  Lan Wang 5,  Jun Liang 5,  Nicholas N Nickerson 6,  Huiyong Hu 5,  Lan Yu 7,  Miaofen Du 7,  Donghong Yan 8,  Summer Park 8,  Janice Kim 8,  Min Xu 8,  Benjamin D Sellers 5,  Hans E Purkey 5,  Nicholas J Skelton 5,  Michael F T Koehler 5,  Jian Payandeh 3,  Vishal Verma 5,  Yiming Xu 2,  Christopher M Koth 3,  Mireille Nishiyama 1
Affiliations

Affiliations

  • 1 Genentech, Inc., Infectious Diseases, South San Francisco, California, USA maryca@gene.com mireille.nishiyama@gmail.com.
  • 2 Genentech, Inc., Biochemical and Cellular Pharmacology, South San Francisco, California, USA.
  • 3 Genentech, Inc., Structural Biology, South San Francisco, California, USA.
  • 4 Genentech, Inc., Pathology, South San Francisco, California, USA.
  • 5 Genentech, Inc., Discovery Chemistry, South San Francisco, California, USA.
  • 6 Genentech, Inc., Infectious Diseases, South San Francisco, California, USA.
  • 7 WuXi AppTec Co. Ltd., Shanghai, China.
  • 8 Genentech, Inc., Translational Immunology, South San Francisco, California, USA.
PMID: 30104274 DOI: 10.1128/AAC.01142-18
Abstract

There is a critical need for new Antibacterial strategies to counter the growing problem of Antibiotic resistance. In Gram-negative bacteria, the outer membrane (OM) provides a protective barrier against Antibiotics and Other environmental insults. The outer leaflet of the outer membrane is primarily composed of lipopolysaccharide (LPS). Outer membrane biogenesis presents many potentially compelling drug targets as this pathway is absent in higher eukaryotes. Most proteins involved in LPS biosynthesis and transport are essential; however, few compounds have been identified that inhibit these proteins. The inner membrane ABC transporter MsbA carries out the first essential step in the trafficking of LPS to the outer membrane. We conducted a biochemical screen for inhibitors of MsbA and identified a series of quinoline compounds that kill Escherichia coli through inhibition of its ATPase and transport activity, with no loss of activity against clinical multidrug-resistant strains. Identification of these selective inhibitors indicates that MsbA is a viable target for new Antibiotics, and the compounds we identified serve as useful tools to further probe the LPS transport pathway in Gram-negative bacteria.

Keywords

ABC transporters; Enterobacteriaceae; Escherichia coli; MsbA; lipopolysaccharide; outer membrane.

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