Reversal of the Antichlamydial Activity of Putative Type III Secretion Inhibitors by Iron

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Abstract
INPs, which are chemically synthesized compounds belonging to a class of acylated hydrazones of salicylaldehydes, can inhibit the growth ofChlamydiaceae. Evidence has been presented that inYersiniaandChlamydiaINPs may affect the type III secretion (T3S) system. In the present study 25 INPs were screened for antichlamydial activity at a concentration of 50 μM, and 14 were able to completely inhibit the growth ofChlamydia trachomatisserovar D in McCoy and HeLa 229 cells. The antichlamydial activities of two of these INPs, INPs 0341 and 0400, were further characterized due to their low cytotoxicity. These compounds were found to inhibitC. trachomatisin a dose-dependent manner; were not toxic to elementary bodies; were cidal at a concentration of ≥20 μM; inhibited allChlamydiaceaetested; and could inhibit the development ofC. trachomatisas determined by the yield of progeny when they were added up to 24 h postinfection. INP 0341 was able to affect the expression of several T3S genes. Compared to the expression in control cultures,lcrH-1,copB, andincA, all middle- to late-expressed T3S genes, were not expressed in the INP 0341-treated cultures 24 to 36 h postinfection. Iron, supplied as ferrous sulfate, as ferric chloride, or as holo-transferrin, was able to negate the antichlamydial 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 antichlamydial activity of INPs is directly or indirectly linked with iron, and this inhibition ofChlamydiahas an effect on the T3S system of this intracellular pathogen.