A Biological Signature for the Inhibition of Outer Membrane Lipoprotein Biogenesis

• Type of Material: Article
• Authors: Kelly M Lehman, Emory University; Hannah C Smith, Emory University; Marcin Grabowicz, Emory University
• Language: English
• Date: 2022-06-13
• Publisher: AMER SOC MICROBIOLOGY
• Publication Version: Final Published Version
• Copyright Statement: © 2022 Lehman et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1128/mbio.00757-22
• Title of Journal or Parent Work: MBIO
• Volume: 13
• Issue: 3
• Start Page: e0075722
• End Page: e0075722
• Grant/Funding Information: This work was supported by grant 1R35GM133509 (to M.G.), fellowship F31AI147589 (to K.M.L.), and training grant T32AI106699 (to H.C.S.).
• Keywords: PROLIPOPROTEIN; Life Sciences & Biomedicine; cell envelope; outer membrane; ANTIBIOTIC TA; CELL-WALL; Science & Technology; MUREIN-LIPOPROTEIN; lipoproteins; antibiotics; stress response; LIPOPOLYSACCHARIDE; Microbiology; ESCHERICHIA-COLI; PEPTIDASE; PEPTIDOGLYCAN; SALMONELLA-TYPHIMURIUM; DIACYLGLYCERYL TRANSFERASE LGT
• Research Categories: Biology, Microbiology; Health Sciences, Medicine and Surgery

Abstract

The outer membrane (OM) of Gram-negative bacteria is an essential organelle that acts as a formidable barrier to antibiotics. Increasingly prevalent resistance to existing drugs has exacerbated the need for antibiotic discovery efforts targeting the OM. Acylated proteins, known as lipoproteins, are essential in every pathway needed to build the OM. The central role of OM lipoproteins makes their biogenesis a uniquely attractive therapeutic target, but it also complicates in vivo identification of on-pathway inhibitors, as inhibition of OM lipoprotein biogenesis broadly disrupts OM assembly. Here, we use genetics to probe the eight essential proteins involved in OM lipoprotein maturation and trafficking. We define a biological signature consisting of three simple assays that can characteristically identify OM lipoprotein biogenesis defects in vivo. We find that several known chemical inhibitors of OM lipoprotein biogenesis conform to the biological signature. We also examine MAC13243, a proposed inhibitor of OM lipoprotein biogenesis, and find that it fails to conform to the biological signature. Indeed, we demonstrate that MAC13243 activity relies entirely on a target outside of the OM lipoprotein biogenesis pathway. Hence, our signature offers simple tools to easily assess whether antibiotic lead compounds target an essential pathway that is the hub of OM assembly.