Francisella Flmx Broadly Affects Lipopolysaccharide Modification And Virulence

The outer membrane protects Gram-negative bacteria from the host environment. Lipopolysaccharide (LPS), a major outermembrane 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 un-characterized 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.