Background Due to the emergence of antibiotic resistance, novel therapies such as host-directed therapeutics (HDT) are being explored as adjunctive therapies against Neisseria gonorrhoeae (Gc). Inhibitors of histone deacetylases (HDACi) are HDTs that restore the balance between host histone acetylases and HDAC, the latter of which are induced by pathogens to enhance infection. We recently reported that sulforaphane (SFN), a natural HDACi, induced effectors with anti-Gc activity in tissue culture cells and reduced colonisation of female mice. Here we tested SFN against the multidrug-resistant strain HO41 and its potential to increase the susceptibility of this strain to antibiotics.
Methods ME180 cervical epithelial cells were treated with 40 or 80 µM SFN or no SFN for 24 h. Cell culture supernatants were then incubated with HO41; in some experiments, sub-lethal concentrations of ciprofloxacin (CIP) or cefixime (CFX) were added to the supernatants. The number of viable Gc recovered after a 4-hour incubation was determined by quantitative culture.
Results Supernatants from cervical cells treated with 40 or 80 µM SFN reduced the survival of strain H041 to 53% and 20%, respectively, relative to recovery from supernatants from untreated cells. Addition of sub-inhibitory concentrations of CIP or CFX to supernatants from SFN-treated (40 µM) cells resulted in a dose-dependent reduction in survival, with 4 µg/ml CIP resulting in 27% survival. Two and 4 µg/ml doses of CFX resulted in 13% and 7% survival, respectively. Addition of 1, 2 and 4 µg/ml of CFX to supernatants from cells treated with 80 uM SFN reduced survival to 15%, 8% and 1%, respectively.
Conclusion The susceptibility of strain HO41 to CIP or CFX is enhanced when tested in tissue culture media containing SFN-induced host effectors. These findings suggest that a combination of HDACi and antibiotics may be an effective adjunct therapy against antibiotic-resistant Gc.
Disclosure of interest statement This project was funded by grant RO1 AI43053 from the US NIH. No pharmaceutical grants were received in the development of this study.