title: Dual Targeting of Cell Wall Precursors by Teixobactin Leads to Cell Lysis.
abstract: Teixobactin represents the first member of a newly discovered class of antibiotics that act through inhibition of cell wall synthesis. Teixobactin binds multiple bactoprenol-coupled cell wall precursors, inhibiting both peptidoglycan and teichoic acid synthesis. Here, we show that the impressive bactericidal activity of teixobactin is due to the synergistic inhibition of both targets, resulting in cell wall damage, delocalization of autolysins, and subsequent cell lysis. We also find that teixobactin does not bind mature peptidoglycan, further increasing its activity at high cell densities and against vancomycin-intermediate Staphylococcus aureus (VISA) isolates with thickened peptidoglycan layers. These findings add to the attractiveness of teixobactin as a potential therapeutic agent for the treatment of infection caused by antibiotic-resistant Gram-positive pathogens.
authors.affiliation: Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, Massachusetts, USA.|Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Homma
authors.affiliation: Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, Massachusetts, USA.|Biology Department, University of Nebraska at Kearney, Kearney, Nebraska, USA.
authors.forename: Austin
authors.initials: A
authors.lastname: Nuxoll
authors.affiliation: Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, Massachusetts, USA.
authors.forename: Autumn Brown
authors.initials: AB
authors.lastname: Gandt
authors.affiliation: Microbial Genetics, University of Tübingen, Tübingen, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Ebner
authors.affiliation: Institute of Pharmaceutical Microbiology, University of Bonn, Bonn, Germany.|German Centre for Infection Research (DZIF), Partner Site Bonn-Cologne, Bonn, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Engels
authors.affiliation: Institute of Pharmaceutical Microbiology, University of Bonn, Bonn, Germany.|German Centre for Infection Research (DZIF), Partner Site Bonn-Cologne, Bonn, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Schneider
authors.affiliation: Microbial Genetics, University of Tübingen, Tübingen, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Götz
authors.affiliation: Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, Massachusetts, USA.
authors.forename: Kim
authors.initials: K
authors.lastname: Lewis
authors.affiliation: Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, Massachusetts, USA brian.patrick.conlon@gmail.com.|Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, North Carolina, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Conlon
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002473:Cell Wall / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D047630:Depsipeptides / Q000494:pharmacology*; D016503:Drug Delivery Systems; D008826:Microbial Sensitivity Tests; D009238:N-Acetylmuramoyl-L-alanine Amidase / Q000378:metabolism; D010457:Peptidoglycan / Q000378:metabolism; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D013682:Teichoic Acids / Q000378:metabolism; D013729:Terpenes / Q000378:metabolism; D020713:Vancomycin Resistance / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D047630:Depsipeptides; D010457:Peptidoglycan; D013682:Teichoic Acids; D013729:Terpenes; C000146:bactoprenol; D009238:N-Acetylmuramoyl-L-alanine Amidase; C000594838:teixobactin