BACKGROUND Treatment of N. gonorrhoeae (Ng) is a major public health challenge as it rapidly develops resistance to antibiotics used to treat it, with approximately half of reported cases today caused by drug resistant strains. In the absence of a vaccine to overcome the current and future threat of multi-drug resistant (MDR) Ng, this project focused on identification and development of novel Ng therapeutics. We investigated products from natural sources, which are often a valuable repository of bioactive compounds.
METHODS/RESULTS We screened a library of 554 natural products and natural product derived compounds using minimum inhibitory (MIC) and minimum bactericidal concentrations (MBC) assays and identified 20 candidates that were active against both susceptible and multi-drug resistant Ng strains. We determined that the MIC and MBC of these compounds ranged between 0.7 and 55 µg/mL against five Ng strains. The MIC of 13/20 compounds was equivalent for MDR Ng strains (WHO K, Z and X), which have distinct antibiotic resistance profiles. Furthermore, the MIC of 13/20 compounds was equivalent between wildtype and MtrE knock-out Ng strains, suggesting that these compounds are not susceptible to drug efflux. We tested the effect of all compounds on metabolic activity of transformed cervical epithelial (tCX) cells and found that 10/20 compounds displayed no toxicity, while 8 weakly suppressed cellular respiration at the highest concentration tested and 2 compounds were highly toxic. Finally, in our in vitro tCX cell infection assay 14/20 compounds reduced Ng CFU by ~90% at MIC and 7/20 compounds reduced Ng CFU 77-96% at ½ MIC, while displaying no cytotoxicity.
CONCLUSION From our natural compound library screen we have identified 6 lead compounds with antibacterial activity against MDR Ng for further development as potential anti-gonococcal therapeutics.