title: Lipopolysaccharide-binding alkylpolyamine DS-96 inhibits Chlamydia trachomatis infection by blocking attachment and entry.
abstract: Vaginally delivered microbicides are being developed to offer women self-initiated protection against transmission of sexually transmitted infections such as Chlamydia trachomatis. A small molecule, DS-96, rationally designed for high affinity to Escherichia coli lipid A, was previously demonstrated to bind and neutralize lipopolysaccharide (LPS) from a wide variety of Gram-negative bacteria (D. Sil et al., Antimicrob. Agents Chemother. 51: 2811-2819, 2007, doi:10.1128/AAC.00200-07). Aside from the lack of the repeating O antigen, chlamydial lipooligosaccharide (LOS) shares general molecular architecture features with E. coli LPS. Importantly, the portion of lipid A where the interaction with DS-96 is expected to take place is well conserved between the two organisms, leading to the hypothesis that DS-96 inhibits Chlamydia infection by binding to LOS and compromising the function. In this study, antichlamydial activity of DS-96 was examined in cell culture. DS-96 inhibited the intercellular growth of Chlamydia in a dose-dependent manner and offered a high level of inhibition at a relatively low concentration (8 μM). The data also revealed that infectious elementary bodies (EBs) were predominantly blocked at the attachment step, as indicated by the reduced number of EBs associated with the host cell surface following pretreatment. Of those EBs that were capable of attachment, the vast majority was unable to gain entry into the host cell. Inhibition of EB attachment and entry by DS-96 suggests that Chlamydia LOS is critical to these processes during the developmental cycle. Importantly, given the low association of host toxicity previously reported by Sil et al., DS-96 is expected to perform well in animal studies as an active antichlamydial compound in a vaginal microbicide.
authors.affiliation: Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas, USA.
authors.forename: Ichie
authors.initials: I
authors.lastname: Osaka
authors.affiliation: Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas, USA pshefty@ku.edu.
authors.forename: P Scott
authors.initials: PS
authors.lastname: Hefty
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D000907:Antibodies, Bacterial / Q000378:metabolism; D001287:Attachment Sites, Microbiological / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002498:Centrifugation; D002690:Chlamydia Infections / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002692:Chlamydia trachomatis / Q000187:drug effects / Q000254:growth & development; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects; D008050:Lipid A / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism*; D051379:Mice; D010710:Phosphates / Q000378:metabolism; D013096:Spermine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity
chemical_list: D000900:Anti-Bacterial Agents; D000907:Antibodies, Bacterial; C534982:DS-96 compound; D008050:Lipid A; D008070:Lipopolysaccharides; D010710:Phosphates; D013096:Spermine