An outer membrane (OM) is the hallmark feature that is often used to distinguish "Gram-negative" bacteria. Our understanding of how the OM is built rests largely on studies of Escherichia coli. In that organism-and seemingly in all species of the Proteobacterial phyla-the essential pathways that assemble the OM each rely on one or more lipoproteins that have been trafficked to the OM. Hence, the lipoprotein trafficking pathway appeared to be foundational for the ability of these bacteria to build their OM. However, such a notion now appears to be misguided. New phylogenetic analyses now show us that lipoprotein trafficking was likely the very last of the essential OM assembly systems to have evolved. The emergence of lipoprotein trafficking must have been a powerful innovation for the ancestors of Proteobacteria, given how it assumed such a central place in OM biogenesis. In this minireview, we broadly discuss the biosynthesis and trafficking of lipoproteins and ponder why the newest OM assembly system (lipoprotein trafficking) has become so key to building the Proteobacterial OM. We examine the diversity among lipoprotein trafficking systems, noting uniting commonalities and highlighting key differences. Current novel antibiotic development is targeted against a small subset of Proteobacterial species that cause severe human diseases; several inhibitors of lipoprotein biosynthesis and OM trafficking have been recently reported that may become new antibiotics. Understanding the diversity in lipoprotein trafficking may yield selective new antibiotics that preferentially kill important human pathogens while sparing species of normal healthy flora.
Keywords: Gram-negative; antibiotics; lipoproteins; outer membrane.