Invited Speaker Australian Society for Microbiology Annual Scientific Meeting 2023

Can histone deacetylase inhibitors have a role in treatment of antimicrobial resistant Neisseria gonorrhoeae infections? (95134)

Van Thaia 1 , Christopher Mullally 1 , Rok Tkavc 2 , Mitalia Sarkar-Tyson 1 , Keith Stubbs 3 , Ann Jerse 2 , Charlene Kahler 1
  1. The Marshall Center for Infectious Diseases Research and Training, School of Biomedical Science, University of Western Australia, Perth
  2. School of Medicine, Uniformed Services , University of the Health Sciences, Bethesda, USA
  3. School of Molecular Sciences, University of Western Australia, CRAWLEY, Western Australia, Australia

Antibiotics are the primary treatment for gonococcal (Ng) infections; however, the emergence of multidrug-resistance (MDR) has rendered almost all classes of antibiotics ineffective. Upon infection of humans Ng initiates a strong Th-17 neutrophil influx in males. The neutrophils cannot kill the bacteria effectively due to resistance to cationic antimicrobial peptides (CAMPs) by the lipo-oligosaccharide phosphoethanolamine lipid A transferase (EptA). Thus, infected neutrophils become a Trojan for further transmission. Histone deacetylase inhibitors (HDACi) are a broad range of compounds that stimulate CAMP expression from human cell lines and we examined whether HDACi treatment alone or in combination with EptA inhibitors could result in cure of immortalised cell lines.

 

INH-2 is a synthetic derivative of compound [137] with improved inhibition towards EptA which was identified using established pipelines. INH-2 and HDACi were tested for toxicity against cell lines using LDH assays. Titration curves of HDACi and INH-2 alone or in combination were tested for their ability to clear infected cell lines (Hela and RAW cell lines).

 

Exposure of WT-Ng to INH-2 restored sensitivity to killing by 6.4-3.2µM LL-37 which was the same MIC as the isogenic ∆eptA mutant. Post-treatment of infected cell lines with INH-2 resulted in the reduction of WT-Ng load to the same degree as the isogenic ∆eptA mutant of each isolate. HDACi treatment was used to stimulate CAMP expression from the cell lines which was measured in the supernatant by bacterial killing. HDACi treatment of the post-infection model with INH-2 resulted in >98% reduction in bacterial load which was sustained for at least 12 hrs.

 

This work demonstrates that HDACi stimulated cells express higher amounts of CAMPs that can reduce bacterial burden but not completely clear the infection in cell lines. However, in the presence of INH-2 which reduces resistance to CAMPs, cell lines can be cleared of these infections for up to 12 hrs. Future work will examine the utility of this approach in mouse models of infection.