Neisseria gonorrhoeae (gonococcus) is the causative agent of gonorrhea and is the second most commonly notified sexually transmitted infection in Australia. This infection causes approximately 100 million new cases per annum and does not result in protective immunity against re-infection. Since there is no vaccine, antibiotics have been used as the sole option for cure and prevention of transmission in the community. Reports of multi-drug resistance in this species and untreatable infections resulting from isolates with decreased sensitivity to ceftriaxone have increased in prevalence since 2013. One strategy for future therapeutics involves the design of drugs to “disarm virulence” which will assist the human immune system to clear the infection.
Multiple potential virulence targets have been identified in the protein folding/repair and membrane biogenesis pathways of the periplasm. Two approaches using fragment based drug design (FBDD) and repurposing approved pharmaceuticals have been used to identify compounds with anti-virulence properties.
The first target is the enzyme lipid A phosphoethanolamine (PEA) transferase A (EptA), which decorates the lipid A headgroups with PEA. This substitution of lipid A results in resistance to cationic antimicrobial peptides (CAMPs) and improves colonization of the mucosal surface. We have determined the 3D structure of EptA which has a helical transmembrane domain linked to a periplasmic facing soluble domain by a single helix positioned along the membrane surface. The structure shows the active site region of the enzyme comprising of residues in both domains. FBDD has identified a family of compounds which can result in an 8-fold decrease in resistance to CAMPs.
The second target is the enzyme, macrophage infectivity potentiator protein (MIP), which is a peptidyl-proline cis/trans isomerase. This family of enzymes is inhibited by rapamycin which is a drug used in ummunotherapy. Repurposing of this drug has identified a scaffold which inhibits MIP and has lost immunoregulatory features.
These studies will aid in the design of novel therapeutic agents for the treatment of multidrug-resistant bacterial infections.