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Infection and Immunity, July 2007, p. 3478-3489, Vol. 75, No. 7
0019-9567/07/$08.00+0     doi:10.1128/IAI.00023-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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

Anatoly Slepenkin,1 Per-Anders Enquist,2 Ulrik Hägglund,3 Luis M. de la Maza,1 Mikael Elofsson,2 and Ellena M. Peterson1*

Department of Pathology and Laboratory Medicine, University of California, Irvine, California,1 Department of Chemistry, Umea University, SE-90187 Umea, Sweden,2 Innate Pharmaceuticals AB, Umestan Foretagspark, SE-90347 Umea, Sweden3

Received 5 January 2007/ Returned for modification 30 January 2007/ Accepted 12 April 2007

INPs, which are chemically synthesized compounds 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 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 of Chlamydia trachomatis serovar 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 inhibit C. trachomatis in a dose-dependent manner; were not toxic to elementary bodies; were cidal at a concentration of ≥20 µM; inhibited all Chlamydiaceae tested; and could inhibit the development of C. trachomatis as 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, and incA, 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 of Chlamydia has an effect on the T3S system of this intracellular pathogen.

* Corresponding author. Mailing address: Department of Pathology and Laboratory Medicine, Medical Science Building, Room D-440, University of California, Irvine, Irvine, CA 92697-4800. Phone: (949) 824-4169. Fax: (949) 824-2160. E-mail: epeterso{at}uci.edu

{triangledown} Published ahead of print on 30 April 2007.

Editor: R. P. Morrison

Infection and Immunity, July 2007, p. 3478-3489, Vol. 75, No. 7
0019-9567/07/$08.00+0     doi:10.1128/IAI.00023-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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