Repurposing salicylamide for combating multidrug-resistant Neisseria gonorrhoeae

Marwa Alhashimi; Abdelrahman Mayhoub; Mohamed N Seleem

doi:10.1128/AAC.01225-19

Repurposing salicylamide for combating multidrug-resistant Neisseria gonorrhoeae

Antimicrob Agents Chemother. 2019 Sep 9;63(12):e01225-19. doi: 10.1128/AAC.01225-19. Epub 2019 Sep 30.

Authors

Marwa Alhashimi¹, Abdelrahman Mayhoub^{2

3}, Mohamed N Seleem^{4

5}

Affiliations

¹ Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN, 47907, USA.
² Department of Pharmaceutical Organic Chemistry, College of Pharmacy, Al-Azhar University, Cairo 11884, Egypt.
³ University of Science and Technology, Nanoscience Program, Zewail City of Science and Technology, October Gardens, 6th of October, Giza 12578, Egypt.
⁴ Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN, 47907, USA mseleem@purdue.edu.
⁵ Purdue Institute of Inflammation, Immunology, and Infectious Disease, West Lafayette, IN, 47907, USA.

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 8-32 μg/ml) with low frequency of resistance <2.4x10^-9 Interestingly, salicylamide did not inhibit growth of bacterial species in the vaginal microflora involved in defense against gonococcal infections, such as Lactobacillus gasseri, L. jensenii, L. johnsonii, and L. crispatus A time-kill assay revealed that salicylamide is a rapidly bactericidal drug as it eradicated a high inoculum of N. gonorrhoeae within 10 hours. 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 pro-inflammatory cytokine IL-8 from endocervical cells infected with N. gonorrhoeae A checkerboard assay revealed that salicylamide exhibited a synergistic interaction with tetracycline and an additive relationship with azithromycin and 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 anti-gonorrheal activity. In conclusion, this study identified salicylamide as a promising candidate for further investigation as a novel treatment option for multidrug-resistant gonorrhea.