Infect Immun. 2007 Apr 30; [Epub ahead of print]
Reversal of the Anti-Chlamydial Activity of Putative Type Three
Secretion Inhibitors by Iron.
Slepenkin A, Enquist PA, Hagglund U, de la Maza LM, Elofsson M,
Peterson EM.
Department of Pathology and Laboratory Medicine, University of
California, Irvine;
Department of Chemistry, Umea University, SE-90187 Umea, Sweden;
Innate Pharmaceuticals AB, Umestan Foretagspark, SE-90347 Umea,
Sweden.
Chemically synthesized compounds, INPs, belonging to a class of
acylated hydrazones of salicylaldehydes can inhibit the growth of
Chlamydiaceae. Evidence has been presented that in Yersinia and
Chlamydia INPs may affect the type three secretion (T3S) system. In
the present study 25 INPs were screened for anti-chlamydial activity
at a concentration of 50 microM and 14 were able to completely inhibit
the growth of Chlamydia trachomatis, serovar D, in McCoy and HeLa 229
cells. The anti-chlamydial activity of two of these INPs, 0341 and
0400, were further characterized due to their low cytotoxicity. These
compounds were found: to inhibit C. trachomatis in a dose dependent
manner; were not toxic to elementary bodies; were cidal at a
concentration of >/=20 microM; inhibited all Chlamydiaceae tested; and
could inhibit the development of C. trachomatis as determined by the
yield of progeny when added up to 24 h post-infection. INP 0341 was
able to affect the gene expression of several T3S genes. Compared to
control cultures, lcrH-1, copB and incA, all middle to late expressed
T3S genes, were not expressed in the INP 0341 treated cultures 24-36 h
post-infection. Iron, supplied as ferrous sulphate, ferric chloride or
as holo-transferrin, was able to negate the anti-chlamydial properties
of the INPs. In contrast, apo-transferrin and other divalent metal
ions tested, were not able to reverse the inhibitory effect of the
INPs. In conclusion, the potent anti-chlamydial activity of INPs
directly or indirectly is linked with iron and this inhibition of
Chlamydia has an effect on the T3S system of this intracellular
pathogen.
PMID: 17470544 [PubMed - as supplied by publisher]
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