Candidate vaginal microbicides with activity against Chlamydia trachomatis and Neisseriagonorrhoeae

• Published in: International journal of antimicrobial agents Vol. 36; no. 2; pp. 145 - 150
• Main Authors: Chu, Hencelyn, Slepenkin, Anatoly, Elofsson, Mikael, Keyser, Pia, de la Maza, Luis M, Peterson, Ellena M
• Format: Journal Article
• Language: English
• Published: Netherlands 01.08.2010
• Subjects: Administration, Intravaginal; Animals; Anti-Infective Agents - pharmacology; Anti-Infective Agents - therapeutic use; Chlamydia Infections - prevention & control; Chlamydia Infections - transmission; Chlamydia trachomatis - drug effects; Disease Models, Animal; Female; Gonorrhea - prevention & control; Gonorrhea - transmission; HeLa Cells; Humans; Hydrazines - pharmacology; Hydrazines - therapeutic use; Lactobacillus - drug effects; Mice; Mice, Inbred C3H; Microbial Sensitivity Tests; Neisseria gonorrhoeae - drug effects; Vagina - microbiology
• ISSN: 0924-8579; 1872-7913
• DOI: 10.1016/j.ijantimicag.2010.03.018

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 microM towards C. trachomatis L2. Three INPs had a MIC <12.5 microM against N. gonorrhoeae. Inhibition 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.