Countering Gram-Negative Antibiotic Resistance: Recent Progress in Disrupting the Outer Membrane with Novel Therapeutics

• Type of Material: Article
• Authors: Kelly M. Lehman, Emory University; Marcin Grabowicz, Emory University
• Language: English
• Date: 2019-12-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2019 by the authors. Licensee MDPI, Basel, Switzerland.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/antibiotics8040163
• Title of Journal or Parent Work: ANTIBIOTICS-BASEL
• Volume: 8
• Issue: 4
• Grant/Funding Information: This work was supported grant 1R35 GM133509 from the National Institute of General Medical Sciences (to M.G.) and by institutional start-up funds from Emory University School of Medicine (to M.G.).
• Keywords: SALMONELLA-TYPHIMURIUM; ESSENTIAL COMPONENT; ENVELOPE-STRESS-RESPONSE; Science & Technology; globomycin; LptD; STRUCTURAL BASIS; LIPOPOLYSACCHARIDE TRANSPORT; REGULATED PROTEOLYSIS; outer membrane; BamA; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI BAMB; Infectious Diseases; Pharmacology & Pharmacy; Life Sciences & Biomedicine; arylomycin; Lol; Lpt; BACTERIAL SIGNAL PEPTIDASE; Bam; BARREL ASSEMBLY MACHINERY
• Research Categories: Health Sciences, Pharmacology; Biology, Virology; Chemistry, Pharmaceutical; Biology, Cell

Abstract

Gram-negative bacteria shield themselves from antibiotics by producing an outer membrane (OM) that forms a formidable permeability barrier. Multidrug resistance among these organisms is a particularly acute problem that is exacerbated by the OM. The poor penetrance of many available antibiotics prevents their clinical use, and efforts to discover novel classes of antibiotics against Gram-negative bacteria have been unsuccessful for almost 50 years. Recent insights into how the OM is built offer new hope. Several essential multiprotein molecular machines (Bam, Lpt, and Lol) work in concert to assemble the barrier and offer a swathe of new targets for novel therapeutic development. Murepavadin has been at the vanguard of these efforts, but its recently reported phase III clinical trial toxicity has tempered the anticipation of imminent new clinical options. Nonetheless, the many concerted efforts aimed at breaking down the OM barrier provide a source of ongoing optimism for what may soon come through the development pipeline. We will review the current state of drug development against the OM assembly targets, highlighting insightful new discovery approaches and strategies.