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Front. Plant Sci. | doi: 10.3389/fpls.2019.01059

Identification of Benzyloxy Carbonimidoyl Dicyanide Derivatives as Novel Type III Secretion System Inhibitors via High-Throughput Screening

 Yi-Nan Ma1, Liang Chen2, Nai-Guo Si2,  Wen-Jun Jiang1, Zhi-Gang Zhou3, Jun-Li Liu2 and  Li-Qun Zhang1*
  • 1China Agricultural University (CAU), China
  • 2Shenyang Sinochem Agrochemicals R&D Co., Ltd., China
  • 3Chinese Academy of Agricultural Sciences, China

The type III secretion system (T3SS) in many Gram-negative bacterial pathogens is regarded as the most critical virulence determinant and an attractive target for novel anti-virulence drugs. In this study, we constructed a T3SS secretion reporter containing the β-lactamase gene fused with a signal peptide sequence of the T3SS effector gene, and established a high-throughput screening system for T3SS inhibitors in the plant pathogenic bacterium Acidovorax citrulli. From a library of 12,000 chemical compounds, we identified a series of benzyloxy carbonimidoyl dicyanide (BCD) derivatives that effectively blocked T3SS-dependent β-lactamase secretion. Substitution of halogens or nitro groups at the para-position on the benzene ring contributed to an increased inhibitory activity. One representative compound, BCD03 (3,4-dichloro-benzyloxy carbonimidoyl dicyanide), dramatically reduced pathogenicity of A. citrulli on melon seedlings, and attenuated hypersensitive responses in the non-host Nicotiana tabacum caused by pathogenic bacteria A. citrulli, Xanthomonas oryzae pv. oryzae and Pseudomonas syringae pv. tomato at sub-MIC concentrations. Western blotting assay further confirmed that BCD03 inhibited effector secretion from the above bacteria via T3SS in the liquid medium. Taken together, our data suggest that BCD derivatives act as novel inhibitors of T3SS in multiple plant bacterial pathogens.

Keywords: Acidovorax, Xanthomonas, Pseudomonas, type III secretion system, hypersensitive response, Virulence inhibitor, benzyloxy carbonimidoyl dicyanide

Received: 15 Mar 2019; Accepted: 05 Aug 2019.

Copyright: © 2019 Ma, Chen, Si, Jiang, Zhou, Liu and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Li-Qun Zhang, China Agricultural University (CAU), Beijing, 100083, Beijing Municipality, China, zhanglq@cau.edu.cn