While antimicrobial resistance (AMR) is seen in both Neisseria gonorrhoeae and Neisseria meningitidis, the former has become resistant to commonly available over-the-counter antibiotic treatments. It is imperative then to develop new therapies that combat current AMR isolates whilst also circumventing the pathways leading to the development of AMR. This review highlights the growing research interest in developing anti-virulence therapies (AVTs) which are directed towards inhibiting virulence factors to prevent infection. By targeting virulence factors that are not essential for gonococcal survival, it is hypothesized that this will impart a smaller selective pressure for the emergence of resistance in the pathogen and in the microbiome, thus avoiding AMR development to the anti-infective. This review summates the current basis of numerous anti-virulence strategies being explored for N. gonorrhoeae.

Many pathogenic gram-negative bacteria have developed mechanisms to increase resistance to cationic antimicrobial peptides by modifying the lipid A moiety. One modification is the addition of phosphoethanolamine to lipid A by the enzyme phosphoethanolamine transferase (EptA). Previously we reported the structure of EptA from Neisseria, revealing a two-domain architecture consisting of a periplasmic facing soluble domain and a transmembrane domain, linked together by a bridging helix. Here, the conformational flexibility of EptA in different detergent environments is probed by solution scattering and intrinsic fluorescence-quenching studies. The solution scattering studies reveal the enzyme in a more compact state with the two domains positioned close together in an n-dodecyl-β-D-maltoside micelle environment and an open extended structure in an n-dodecyl-phosphocholine micelle environment. Intrinsic fluorescence quenching studies localize the domain movements to the bridging helix. These results provide important insights into substrate binding and the molecular mechanism of endotoxin modification by EptA.