Candidate vaginal microbicides with activity against Chlamydia trachomatis and Neisseriagonorrhoeae

Abstract

Vaginal microbicides with activity towards organisms that cause sexually transmitted infections have been proposed as a strategy to reduce transmission. Small-molecule inhibitors of Chlamydia trachomatis serovar D belonging to the class of salicylidene acylhydrazides (INPs) have been shown to work through a mechanism that involves iron restriction. Expanding on this work, ten INPs were tested against a lymphogranuloma venereum strain of C. trachomatis serovar L2, Neisseria gonorrhoeae, and hydrogen peroxide-producing Lactobacillus crispatus and Lactobacillus jensenii. Seven INPs had minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations of <50 µM towards C. trachomatis L2. Three INPs had an MIC <12.5 µM against N. gonorrhoeae. Inhibition by was reversed by iron, holo-transferrin and holo-lactoferrin but not by the iron-poor forms of these compounds. The compounds exhibited no bactericidal activity toward Lactobacillus. The INPs were not cytotoxic to HeLa 229 cells. When INP 0341 was tested in a mouse model of a Chlamydia vaginal infection there was a significant reduction in the number of mice shedding C. trachomatis up to 4 days after infection (P < 0.01). In summary, select INPs are promising vaginal microbicide candidates as they inhibit the growth of two common sexually transmitted organisms in vitro, are active in a mouse model against C. trachomatis, are not cytotoxic and do not inhibit organisms that compose the normal vaginal flora.

In Vitro Activity of Quaternary Ammonium Surfactants against Streptococcal, Chlamydial, and Gonococcal Infective Agents

“…Thus, the End1 immortalized epithelial cell line from normal human endocervical tissue and HeLa epithelial cells originating from an adenosquamous carcinoma of the cervix were used as models of female lower genital tract epithelial cells. It has been shown that both cell lines support chlamydial growth (20,21) as well as the attachment and intracellular uptake of piliated N. gonorrhoeae strains (17,18).…”

Influence of chelation strength and bacterial uptake of gallium salicylidene acylhydrazide on biofilm formation and virulence of Pseudomonas aeruginosa

“…Following these results we hypothesized that a hydrazone with effect on ExoS secretion should become further enhanced through complexation with Ga(III) and that this effect would be correlated to the metal chelation strength of the ligand. To test this hypothesis we selected a hydrazone, N'-(5-chloro-2-hydroxy-3-methylbenzylidene)-2,4-dihydroxybenzhydrazide (INP0341, or ME0329), that previously has been described to have a good antibacterial effect against other Gramnegative bacteria [14,15], and that showed to have an effect against the T3SS in P. aeruginosa in preliminary experiments. We used P. aeruginosa as a relevant model organism in this context, since it is an opportunistic pathogen giving rise to a range of different infections in humans.…”

In vitro anti-HIV-1 activity of salicylidene acylhydrazide compounds

“…However, at least in the case of Chlamydia spp., the salicylidene acylhydrazides exert an antibacterial effect either directly or indirectly by limiting iron availability to host cells [4]. We have recently shown that sexually transmitted pathogens, including C. trachomatis and Neisseria gonorrhoeae , can be inhibited in vitro by μM concentrations of selected salicylidene acylhydrazides [5]. In the case of Chlamydia, these compounds were further shown to protect mice from a vaginal challenge [6].…”