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 lM) was synergistic with low quercetin and luteolin concentrations (0.39 and 1.56 lM), whereas 10 lM isradipine was synergistic with high quercetin, rhamnetin and octyl gallate concentrations (12.5 lM and 100 lM). 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 lM 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.

Antimicrobial Effect of Natural Polyphenols With or Without Antibiotics onChlamydia pneumoniaeInfectionIn Vitro

“…16 Recently, resistance rates have doubled, 30 resulting in increased interest in alternative/adjunctive therapies, including antioxidants from plants and other natural sources. 11 With rising rates of C. pneumoniae resistance to clarithromycin or ofloxacin, our results suggest the possibility of adding one of these antioxidants to therapeutic regimes for C. pneumoniae infection for enhanced activity, in accordance with the data obtained by Salin et al 40 . Further studies in animal models and humans are required to evaluate the potential of such combinations.…”

“…2 A large number of antimicrobial substances called phytoalexins (including flavonoids) are found in nature, and they make up a variable group of compounds playing important roles in the natural defense against several organisms. 40 Resveratrol is a natural compound produced by some spermatophytes, such as grapes and other plants 11 and has been shown to be anti-inflammatory. The effects of flavonols and flavones on the enzymes regulating cell division and proliferation and inflammatory and immune responses are well documented.…”

Natural Products for the Treatment of Chlamydiaceae Infections

“…While isradipine was synergistic with high concentrations of luteolin and quercetin, verapamil was synergistic with low concentrations of the same polyphenols. Thapsigargin had the greatest synergistic effect, significantly increasing the chlamydial growth inhibitory effect of polyphenols [56]. However, although this provides interesting insights, it should be highlighted that the synergistic use of calcium modulators in humans may lead to significant side effects.…”

Recent advances in technologies for developing drugs againstChlamydia pneumoniae

“…In epithelial cells L-type specific (isradipin) as well as unspecific (verapamil) calcium channel blockers rather improved than suppressed C. pneumoniae growth [45], which reflects the indigenously different infection state in the two cell types and the properties of calcium channel blockers as infection modulators rather than chlamydial growth inhibitors. Effects of calcium channel blockers on C.pneumoniae have also been studied in combination with the phenolic compounds quercetin, rhamnetin and luteolin[45]. These three naturally occurring compounds have been shown to suppress C. pneumoniae growth in vitro and in vivo[38,46,47], and the connection of high dietary phenolic compound intake to lowered atheroschlerosis risk has opened the speculations on the relevance of also antichlamydial effects in this respect Combining quercetin, rhamnetin or luteolin with isradipin or verapamil did not…”

“…in improved C. pneumoniae growth inhibition in epithelial cells,but combining the same phenolic compounds with thapsigargin, a modulator of endoplasmic reticulum transport protein responsible for intracellular calcium homeostasis, was reported to result in a significant synergistic effect on C.pneumoniae growth[45]. Impact of such combinations on C. pneumoniaeinfected macrophages or other models of the persistent infection is not known, and in vivo studies with the phenolic compounds should take into account the well-known anti-inflammatory effects besides the direct antichlamydial activities, but further studies on combining the phenolic compounds would be of importance not least due to the abundance of these compounds in our daily diets.The significance of immunomodulatory effects on the overall outcome of antichlamydial therapy is presented also by the effects of statins, widely used lipid lowering drugs, on C. pneumoniae infections.…”