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Francisella FlmX broadly affects lipopolysaccharide modification and virulence
Emory Antibiotic Resistance Center, Emory University School of Medicine, GA, Atlanta, United States; Emory Vaccine Center, Emory University School of Medicine, GA, Atlanta, United States; Yerkes National Primate Research Center, Emory University School of Medicine, GA, Atlanta, United States; Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, GA, Atlanta, United States.
Department of Biochemistry, Duke University School of Medicine, NC, Durham, United States.
Emory Vaccine Center, Emory University School of Medicine, GA, Atlanta, United States; Yerkes National Primate Research Center, Emory University School of Medicine, GA, Atlanta, United States; Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, GA, Atlanta, United States.
Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
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2021 (English)In: Cell Reports, E-ISSN 2211-1247, Vol. 35, no 11, article id 109247Article in journal (Refereed) Published
Abstract [en]

The outer membrane protects Gram-negative bacteria from the host environment. Lipopolysaccharide (LPS), a major outer membrane constituent, has distinct components (lipid A, core, O-antigen) generated by specialized pathways. In this study, we describe the surprising convergence of these pathways through FlmX, an uncharacterized protein in the intracellular pathogen Francisella. FlmX is in the flippase family, which includes proteins that traffic lipid-linked envelope components across membranes. flmX deficiency causes defects in lipid A modification, core remodeling, and O-antigen addition. We find that an F. tularensis mutant lacking flmX is >1,000,000-fold attenuated. Furthermore, FlmX is required to resist the innate antimicrobial LL-37 and the antibiotic polymyxin. Given FlmX's central role in LPS modification and its conservation in intracellular pathogens Brucella, Coxiella, and Legionella, FlmX may represent a novel drug target whose inhibition could cripple bacterial virulence and sensitize bacteria to innate antimicrobials and antibiotics.

Place, publisher, year, edition, pages
Elsevier, 2021. Vol. 35, no 11, article id 109247
Keywords [en]
cationic antimicrobial peptide, flippase, lipid A, lipopolysaccharide, polymyxin resistance
National Category
Microbiology in the medical area Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:umu:diva-186362DOI: 10.1016/j.celrep.2021.109247ISI: 000661869600009PubMedID: 34133919Scopus ID: 2-s2.0-85107905377OAI: oai:DiVA.org:umu-186362DiVA, id: diva2:1581682
Funder
NIH (National Institute of Health), AI098800, I01 BX002788Swedish Research Council, 2013-4581, 2013-8621Available from: 2021-07-23 Created: 2021-07-23 Last updated: 2024-01-17Bibliographically approved

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Golovliov, IgorSjöstedt, Anders

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Cell Reports
Microbiology in the medical areaMedical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)

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