Two Novel Resazurin Derivatives, R-mor and R-MeAll, Exhibit Robust Antimicrobial Activity Against Neisseria gonorrhoeae.

Abstract

Antibiotic resistance is an urgent public health threat. The CDC estimates there are approximately 2.8 million new cases of antibiotic-resistant infections annually resulting in 35,000 deaths and billions of dollars in health care costs. The development of new drugs is imperative to combat this crisis and prevent the loss of additional lives from once “curable” diseases. Resazomycins, a novel family of antibiotics, have bactericidal activity against Neisseria gonorrhoeae.  One resazomycin, resorufin pentyl ether (RPE), significantly reduces vaginal colonization by N. gonorrhoeae in a mouse model of infection.  Repeated administration of RPE, however, fails to clear the infection, in contrast to a single dose of ceftriaxone, an antibiotic commonly used to treat gonorrhea, which clears the infection within 24 hours. Further characterization of resazomycins revealed the efficacy of these compounds is limited by interaction with serum albumin and reduced oxygen concentrations found within mammalian tissues.  Therefore, we hypothesize novel resazurin analogs that maintain antimicrobial activity in the presence of serum albumin and low oxygen will have improved therapeutic efficacy in vivo.  Resazurin has been chemically modified to generate derivatives with altered electrophilicity.  Two derivatives, resorufin morpholinoethyl ether (R-mor) and resorufin methylallyl ether (R-MeAll), exhibited robust antimicrobial activity against N. gonorrhoeae, and maintained antimicrobial activity in the presence of serum albumin. Further characterization of R-mor and R-MeAll revealed minimal changes in human endometrial cell viability following incubation with these compounds.  Future investigations will focus on evaluating the pharmacokinetics and in vivo efficacy of R-mor and R-MeAll in a mouse model of gonorrhea.