AUTHOR=Kahler Charlene M. , Nawrocki K. L. , Anandan A. , Vrielink Alice , Shafer William M. 

TITLE=Structure-Function Relationships of the Neisserial EptA Enzyme Responsible for Phosphoethanolamine Decoration of Lipid A: Rationale for Drug Targeting

JOURNAL=Frontiers in Microbiology

VOLUME=Volume 9 - 2018

YEAR=2018

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2018.01922

DOI=10.3389/fmicb.2018.01922

ISSN=1664-302X

ABSTRACT=Bacteria cause disease by two general mechanisms: the action of their toxins on host cells and induction of a pro-inflammatory response that can lead to a deleterious cytokine/chemokine response (e.g., the so-called cytokine storm) often seen in bacteremia/septicemia.  These major mechanisms may overlap due to the action of surface structures that can have direct and indirect actions on phagocytic or non-phagocytic cells. In this respect, the lipid A (endotoxin) component of lipopolysaccharide (LPS) possessed by Gram-negative bacteria has been the subject of literally thousands of studies over the past century that clearly identified it as a key virulence factor in endotoxic shock. In addition to its capacity to modulate inflammatory responses, endotoxin can also modulate bacterial susceptibility to host antimicrobials, such as the host defense peptides termed cationic antimicrobial peptides.  This review concentrates on the phosphoethanolamine (PEA) decoration of lipid A in the pathogenic species of the genus Neisseria (N. gonorrhoeae and N. meningitidis).   PEA decoration of lipid A is mediated by the enzyme EptA (formerly termed LptA) and promotes resistance to innate defense systems, induces the pro-inflammatory response and can influence the in vivo fitness of bacteria during infection. These important biological properties have driven efforts dealing with the biochemistry and structural biology of EptA that will facilitate the development of potentially therapeutic inhibitors that block PEA addition to lipid A.  We propose that this strategy would render bacteria susceptible to innate host defenses and reduce the potentially damaging action of the pro-inflammatory response during infection.  We posit that EptA inhibitors would serve as adjunctive therapeutics to counteract multidrug-resistant strains of N. gonorrhoeae that threaten the efficacy of currently used antibiotics.