Cell-based screen for discovering lipopolysaccharide biogenesis inhibitors

Ge Zhang, Vadim Baidin, Karanbir S. Pahil, Eileen Moison, David Tomasek, Nitya S. Ramadoss, Arnab K. Chatterjee, Case W. McNamara, Travis S. Young, Peter G. Schultz, Timothy C. Meredith, Daniel Kahne

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

New drugs are needed to treat gram-negative bacterial infections. These bacteria are protected by an outer membrane which prevents many antibiotics from reaching their cellular targets. The outer leaflet of the outer membrane contains LPS, which is responsible for creating this permeability barrier. Interfering with LPS biogenesis affects bacterial viability. We developed a cell-based screen that identifies inhibitors of LPS biosynthesis and transport by exploiting the nonessentiality of this pathway in Acinetobacter. We used this screen to find an inhibitor of MsbA, an ATP-dependent flippase that translocates LPS across the inner membrane. Treatment with the inhibitor caused mislocalization of LPS to the cell interior. The discovery of an MsbA inhibitor, which is universally conserved in all gram-negative bacteria, validates MsbA as an antibacterial target. Because our cell-based screen reports on the function of the entire LPS biogenesis pathway, it could be used to identify compounds that inhibit other targets in the pathway, which can provide insights into vulnerabilities of the gram-negative cell envelope.

Original languageEnglish (US)
Pages (from-to)6834-6839
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number26
DOIs
StatePublished - Jun 26 2018

All Science Journal Classification (ASJC) codes

  • General

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