title: 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 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Irvine, CA 92697-4800, USA.
authors.forename: Hencelyn
authors.initials: H
authors.lastname: Chu
authors.forename: Anatoly
authors.initials: A
authors.lastname: Slepenkin
authors.forename: Mikael
authors.initials: M
authors.lastname: Elofsson
authors.forename: Pia
authors.initials: P
authors.lastname: Keyser
authors.forename: Luis M
authors.initials: LM
authors.lastname: de la Maza
authors.forename: Ellena M
authors.initials: EM
authors.lastname: Peterson
mesh_terms: D000282:Administration, Intravaginal; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002690:Chlamydia Infections / Q000517:prevention & control* / Q000635:transmission; D002692:Chlamydia trachomatis / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D006069:Gonorrhea / Q000517:prevention & control* / Q000635:transmission; D006367:HeLa Cells; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology* / Q000627:therapeutic use; D007778:Lactobacillus / Q000187:drug effects; D051379:Mice; D008809:Mice, Inbred C3H; D008826:Microbial Sensitivity Tests; D009344:Neisseria gonorrhoeae / Q000187:drug effects*; D014621:Vagina / Q000382:microbiology*
chemical_list: D000890:Anti-Infective Agents; D006834:Hydrazines; C541377:INP 0341