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Ritchie, William; Neal, William J.; Bush, David M.; Pilkey, Orrin H.; Blasco, F.; Aizpuru, M.; Besnehard, J.; Bird, Eric; Din, Ndongo; Williams, A. T.; Tudor, D. T.; Gregory, Murray R.; May, Vincent; Pirazzoli, Paolo A.; Trenhaile, Alan S.; Stone, Gregory W.; Muller, Robert A.; Andrew, J; Cooper, J. Andrew G.; Yáñez‐Arancibia, Alejandro; Osterkamp, W. R.; Morton, Robert A.; Inman, Douglas L.; Jenkins, Scott A.; Masters, Patricia M.; Galgano, Francis A.; Leatherman, Stephen P.; Doody, J. Pat; Morang, Andrew; Gorman, Laurel T.; Healy, Terry R.

doi:10.1007/1-4020-3880-1_13

Cited by 1 publication

(1 citation statement)

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“…Some data, however, suggest that effector unfolding and export are fueled by proton motive force at the membrane, rather than ATPase. [16] Regardless of what the precise function of T3SS ATPase is, several studies demonstrated the necessity of functional ATPase for proper T3SS functioning and full virulence in several pathogens, including E. coli, [17] Burkholderia pseudomallei, [18] Yersinia pestis, [13] and Yersinia enterocolitica. [19] Discovery of T3SS ATPase inhibitors was reported by Swietnicki et al [13] The authors used homology modeling to create a model of Y. pestis YscN T3SS ATPase based on the structure of E. coli EscN protein, and screened ZINC database [20] against this model to identify 50 compounds selected for experimental testing.…”

Section: Introductionmentioning

confidence: 99%

Identification of chlamydial T3SS inhibitors through virtual screening against T3SS ATPase

et al. 2017

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Chlamydia trachomatis is a widespread sexually transmitted pathogen that resides within a special vacuole inside host cells. Although acute infection can be treated with antibiotics, chlamydia can enter persistent state, leading to chronic infection that is difficult to cure. Thus, novel anti-chlamydial compounds active against persistent chlamydia are required. Chlamydiae rely upon type III secretion system (T3SS) to inject effector proteins into host cell cytoplasm, and T3SS inhibitors are viewed as promising compounds for treatment of chlamydial infections. C. trachomatis ATPase SctN is an important T3SS component and has not been targeted before. We thus used virtual screening against homology modeled SctN structure to search for SctN inhibitors. Selected compounds were tested for their ability to inhibit chlamydial survival and development within eukaryotic cells, and for the ability to suppress normal T3SS functioning. We identified two compounds that were able to block normal protein translocation through T3SS and inhibit chlamydial survival within eukaryotic cells in 50-100 μm concentrations. These two novel T3SS inhibitors also possessed relatively low toxicity toward eukaryotic cells. A small series of derivatives was further synthesized for the most active of two inhibitors to probe SAR properties.

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