Inhibition of Growth of Chlamydia trachomatis by the Calcium Antagonist Verapamil

Shainkin-Kestenbaum, R.; Winikoff, Y.; Kol, R.; Chaimovitz, Cidio; Sarov, Israel

doi:10.1099/00221287-135-6-1619

Cited by 8 publications

(6 citation statements)

References 11 publications

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“…medium. The 98% reduction in the number of chlamydial inclusions in MAPT/AM-treated McCoy cells is in agreement with the results of Shainkin-Kestenbaum et al(34), who showed that the calcium antagonist Verapamil almost completely inhibited the growth of C trachomatis in African green monkey kidney cells. These results suggest that both the intracellular redistribution of C. trachomatis and the subsequent development of inclusions are dependent on a critical concentration of intracellular Ca2+.Attachment or ingestion of chlamydiae does not seem to cause any detectable release or influx of Ca2' across the cell membrane as determined by the Ca2+-dependent fluorescence of Fura-2.…”

supporting

confidence: 91%

Roles of Ca2+ and F-actin in intracellular aggregation of Chlamydia trachomatis in eucaryotic cells

et al. 1993

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The effect of intracellular free Ca2+ ([Ca2]11) on the intracellular aggregation of Chlamydia trachomatis serovars L2 and E in McCoy and HeLa cells is investigated. Loading the cells with the Ca2+ chelator M.APT/AM (1,2-bis-5-methyl-amino-phenoxylethane-N,N,n'-tetra-acetoxymethyl acetate), thereby decreasing the [Ca2+], from 67 to 19 nM, decreased the number of cells with a local aggregation of chlamydiae in a dose-dependent manner. Neither the attachment nor the uptake of elementary bodies (EBs) was, however, affected after depletion of Ca2+ from the cells. There was no significant difference in the level of measured [Ca211i between infected and uninfected cells. Reducing the [Ca2+]i also significantly inhibited chlamydial inclusion formation. Differences in the organization of the actin filament network were observed in response to [Ca2+], depletion. In Ca2+-depleted cells, where few EB aggregates were formed, few local accumulations of F-actin were observed in the cytosol. These results suggest that the aggregation of EBs in eucaryotic cells requires a normal homeostasis of intracellular Ca2+. By affecting F-actin reorganization and putatively certain Ca2+-binding proteins, [Ca2]i1 plays a vital role in the infectious process of chlamydiae.Chlamydiae are obligate intracellular parasites of eucaryotic cells and cause a wide spectrum of human diseases (33). As intracellular parasites, chlamydiae have developed the morphologically distinct infectious elementary body (EB) which is metabolically inert and resistant to the inimical extracellular environment. The noninfectious reticulate body is the metabolically active and replicating form (28). The developmental cycle starts when the EB attaches to and enters the host cell. It remains within an endosome, where it changes to the reticulate body, which divides by binary fission within the endosome. After a number of divisions, the reticulate bodies reorganize into EBs, producing the characteristic inclusion. It is not clear how and why the chlamydial endosome avoids fusion with host cell lysosomes (11). Earlier studies have suggested that multiple Chlamydia trachomatis endosomes fuse at some time after infection (4, 6). These findings were supported by ultrastructural studies (19,41) indicating that fusion occurs very shortly after infection. Ridderhof and Barnes (31) have shown that C. trachomatis-containing phagosomes fuse with each other in a microfilament-dependent process. However, how this fusion is controlled is unclear.The responsiveness of cells to a wide range of stimuli depends upon internal signaling systems such as cyclic nucleotides (cAMP, cGMP) (22) and intracellular free Ca2+

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supporting

confidence: 91%

Roles of Ca2+ and F-actin in intracellular aggregation of Chlamydia trachomatis in eucaryotic cells

et al. 1993

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“…The Ca 2+ channel inhibitors have been shown to be of value in antimicrobial therapy by interacting with antimicrobial compounds and helping to prevent resistance. 14,25,26 Azenabor et al 16 demonstrated that an L-type Ca 2+ channel blocker, nifedipine, may enhance the antichlamydial effect of doxycycline in persistent infection cell model. Nifedipine treatment of macrophages infected with C. pneumoniae downregulated chlamydial hsp60 mRNA expression and upregulated major outer membrane protein expression, thus shifting the infection toward a form, which is more susceptible to antibiotic treatment.…”

Section: Discussionmentioning

confidence: 99%

“…13 High doses of verapamil have been shown to inhibit the growth of Chlamydia, 14 and most interestingly, Ca 2+ channel blockers have been shown to improve antibiotic susceptibility of persistent C. pneumoniae infection, presumably by reactivating the persistent infection to more easily treatable acute infection. 15,16 We have previously shown that phenolic compounds, common in our daily food, are potent and valid inhibitors of C. pneumoniae, in vitro and in vivo, even with doses achievable from the nutritional sources.…”

Section: Introductionmentioning

confidence: 99%

Effects of coadministration of natural polyphenols with doxycycline or calcium modulators on acute Chlamydia pneumoniae infection in vitro

et al. 2011

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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.

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“…Ca2", another intracellular mediator regulating cellular activities, was also shown to be important in the growth and development of chlamydiae. Treatment of C. trachomatisinfected cells with the calcium antagonist verapamil interfered with chlamydial development, inhibiting RB-to-EB differentiation (104).…”

Section: Other Potential Mediators Of Persistencementioning

confidence: 99%

Persistent chlamydiae: from cell culture to a paradigm for chlamydial pathogenesis.

Beatty

Morrison

Byrne

1994

Microbiological Reviews

401

234

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Inhibition of Growth of Chlamydia trachomatis by the Calcium Antagonist Verapamil

Cited by 8 publications

References 11 publications

Roles of Ca2+ and F-actin in intracellular aggregation of Chlamydia trachomatis in eucaryotic cells

Roles of Ca2+ and F-actin in intracellular aggregation of Chlamydia trachomatis in eucaryotic cells

Effects of coadministration of natural polyphenols with doxycycline or calcium modulators on acute Chlamydia pneumoniae infection in vitro

Persistent chlamydiae: from cell culture to a paradigm for chlamydial pathogenesis.

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