title: Effects of coadministration of natural polyphenols with doxycycline or calcium modulators on acute Chlamydia pneumoniae infection in vitro.
abstract: Besides small molecules from medicinal chemistry, natural products are still major sources of innovative therapeutic agents for various conditions, including infectious diseases. Here we present the first attempt to design a combination treatment targeted against Chlamydia pneumoniae infection using coadministration of natural phenolics with calcium (Ca(2+)) modulators, and also the concomitant administration of these compounds with doxycycline. An in vitro acute C. pneumoniae model in human lung epithelial cells was used and Loewe additivity model was applied to evaluate the effects. In general, the phenolic compounds, quercetin, luteolin, rhamnetin and octyl gallate did not improve the antichlamydial effect of doxycycline, and, in some cases, resulted in antagonistic effects. The combination of doxycycline and Ca(2+) modulators (isradipine, verapamil and thapsigargin) was at most additive, and at subinhibitory concentrations of doxycycline, often even antagonistic. The Ca(2+) modulators showed no inhibitory effects on C. pneumoniae growth alone, whereas the coadminstration of Ca(2+) modulators with phenolic compounds resulted in potentiation of the antichlamydial effect of phenolic compounds. Verapamil (100 μM) was synergistic with low quercetin and luteolin concentrations (0.39 and 1.56 μM), whereas 10 μM isradipine was synergistic with high quercetin, rhamnetin and octyl gallate concentrations (12.5 μM and 100 μM). Use of thapsigargin with the phenolic compounds resulted in the most intense synergism. Interaction indices 0.12 and 0.14 were achieved with 0.39 μM luteolin and 10 and 100 nM thapsigargin, respectively. To conclude, the observed results indicate that the Ca(2+) modulators potentiate the antichlamydial effects of the phenolic compounds.
authors.affiliation: Pharmaceutical Sciences, Department of Biosciences, Abo Akademi University, BioCity, Artillerigatan 6 A, Turku, Finland.
authors.forename: Olli P
authors.initials: OP
authors.lastname: Salin
authors.forename: Leena L
authors.initials: LL
authors.lastname: Pohjala
authors.forename: Pekka
authors.initials: P
authors.lastname: Saikku
authors.forename: Heikki J
authors.initials: HJ
authors.lastname: Vuorela
authors.forename: Maija
authors.initials: M
authors.lastname: Leinonen
authors.forename: Pia M
authors.initials: PM
authors.lastname: Vuorela
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002118:Calcium / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016993:Chlamydophila pneumoniae / Q000187:drug effects*; D004318:Doxycycline / Q000494:pharmacology*; D004357:Drug Synergism; D004847:Epithelial Cells / Q000187:drug effects / Q000382:microbiology; D006801:Humans; D059808:Polyphenols / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D059808:Polyphenols; D004318:Doxycycline; D002118:Calcium