# Innovation and Application of the Type III Secretion System Inhibitors in Plant Pathogenic Bacteria
## 3 Discovery of T3 SS Inhibitors in Plant Pathogens and Their Regulatory Mechanisms
### Plant Phenolic Compounds as T3 SS Inhibitors  
Plant phenolic compounds are one of the most widespread secondary metabolites in plants. They range from low molecular weight and single aromatic ringed compounds to large and complex-polyphenols and are involved in diverse physiological activities in plants, such as pigmentation, growth, and defense mechanisms [123]. Plant phenolic compounds also function as signal molecules that either induce or repress the microbial gene expression during the interactions between plants and microbes [124]. As the expression of _D. dadantii_ T3 SS genes was induced in planta [125], [PERSON] et al. discovered that two plant phenolic compounds, \(o\)-coumaric acid and \(t\)-cinnamic acid, positively regulated the expression of T3 SS genes in _D. dadantii_[32]. \(o\)-coumaric acid upregulated _hrpL_ at the post-transcriptional level via the RsmA/RsmB system and had no impact on the HrpX/HrpY-HrpS-HrpPL pathway. Although \(o\)-coumaric acid and \(t\)-cinnamic acid are the biosynthetic precursors of salicylic acid, which plays an important role in plant defense responses [126; 127], application of salicylic acid did not affect the expression of T3 SS in _D. dadantii_[32]. \begin{table}
\begin{tabular}{c c c} \hline \hline
**Compound** & **Structure** & **Known Modes of Action on T3 SS in Plant Pathogens** & **References** \\ \hline Salicylic acid & Inhibit T3 SS in _E. amylovora_. & [115] \\
4-methoxy-cinnamic acid & Inhibit T3 SS via _E. amylovora_. & [115] \\  & Inhibit T3 SS via _E. amylovora_. & [115] \\  & Inhibit T3 SS via _E. amylovora_. & [115] \\  & Inhibit T3 SS via _E. amylovora_. & [115] \\  & Inhibit T3 SS via _E. amylovora_. & [116] \\  & Inhibit  
To identify potential phenolic compounds as T3 SS inhibitors, [PERSON] and colleagues evaluated the effects of 29 analogs and isomers of \(o\)-coumaric acid and \(t\)-cinnamic acid on the transcriptional activity of _hrpA:sfp_ fusion in _D. dadantii_. One compound, \(p\)-coumaric acid, was shown to repress the expression of T3 SS genes via the HrpS-HrpL pathway, as the addition of 100 \(\upmu\)M \(p\)-coumaric acid significantly reduced the transcriptional activities and mRNA levels of _hrpS_ and _hrpL_ without affecting the bacterial growth [117]. \(p\)-coumaric acid is an intermediate in the phenylpropanoid biosynthesis pathway. Phenylpropanoids are plant secondary metabolites that act as defense molecules in response to microbial attack [128; 129]. It is worth noting that the discovery of \(p\)-coumaric acid as a T3 SS inhibitor has provided fundamental aspects for compound modification and greatly encouraged the innovation of chemically synthesized plant phenolic compound derivatives. A subsequent library screening of 50 \(p\)-coumaric acid derivatives identified _trans_-4-hydroxycinnamohydroxamic acid as a T3 SS inhibitor in _D. dadantii_. The same study found that this synthetic compound increased the inhibitory potency towards T3 SS by eightfold compared with the naturally occurring \(p\)-coumaric acid [118]. Furthermore, _trans_-4-hydroxycinnamohydroxamic acid was shown to repress _hrpL_ transcriptionally through both the RpNoN-HrpL pathway and the HrpX/HrpY-HrpS-HrpL pathway. _Trans_-4-hydroxycinnamohydroxamic acid repressed _rsmB_ via unknown mechanisms, negatively contributing to the post-transcriptionally regulation of _hrpL_[118]. Using similar strategies as [PERSON] et al. [117; 118], [PERSON] and colleagues reported several plant phenolic compounds and derivatives that can modulate T3 SS in _E. amylovora_[115]. \(o\)-coumaric acid and \(t\)-cinnamic acid, which induced the expression of T3 SS in _D. dadantii_[32], repressed the _E. amylovora_ T3 SS. The T3 SS inhibitors of _E. amylovora_ also include benzoic acid, salicylic acid, and 4-methoxy-cinnamic acid. Benzoic acid negatively regulated _hrpS_ expression, while 4-methoxy-cinnamic acid repressed HrpL, respectively. HR analysis demonstrated that co-infiltration of _E.