Repurposing Salicylamide for Combating Multidrug-Resistant Neisseria gonorrhoeae

ABSTRACT

The U.S. Centers for Disease Control and Prevention (CDC) lists Neisseria gonorrhoeae as one of the most urgent antibiotic-resistant threats in the United States. This is due to the emergence of clinical isolates that have developed resistance to nearly every antibiotic used to treat gonorrhea and highlights the critical need to find new therapeutics. The present study discovered salicylamide, an analgesic and antipyretic drug, has antibacterial activity against 40 different antibiotic-resistant strains of N. gonorrhoeae (MIC, 8 to 32 μg/ml) with low frequency of resistance <2.4 × 10⁻⁹. Interestingly, salicylamide did not inhibit growth of bacterial species in the vaginal microflora involved in defense against gonococcal infections, such as Lactobacillus gasseri, Lactobacillus jensenii, Lactobacillus johnsonii, and Lactobacillus crispatus. A time-kill assay revealed that salicylamide is a rapidly bactericidal drug, as it eradicated a high inoculum of N. gonorrhoeae within 10 h. Salicylamide was superior to the drug of choice, ceftriaxone, in reducing the burden of intracellular N. gonorrhoeae by 97% in infected endocervical cells. Furthermore, salicylamide outperformed ceftriaxone in reducing expression of the proinflammatory cytokine interleukin 8 (IL-8) from endocervical cells infected with N. gonorrhoeae. A checkerboard assay revealed that salicylamide exhibited a synergistic interaction with tetracycline and additive relationships with azithromycin, ciprofloxacin, and ceftriaxone. A more in-depth investigation of the structure-activity relationship of derivatives of salicylamide revealed the amide and hydroxyl groups are important for antigonorrheal activity. In conclusion, this study identified salicylamide as a promising candidate for further investigation as a novel treatment option for multidrug-resistant gonorrhea.