# Innovation and Application of the Type III Secretion System Inhibitors in Plant Pathogenic Bacteria
## 1 Introduction  
Type III secretion systems (T3 SSs) are well-studied protein secretion/translocation systems found in almost all Gram-negative bacterial pathogens of plants and animals [1; 2]. Structurally, the T3 SSs are highly conserved among bacteria. They are syringe-like nanomachines consisting of inner and outer membrane rings, known as a basal body, and an apparatus that enables bacteria to inject diverse effector proteins directly into the host cell cytoplasm, which participate in the regulation of host cell functions to benefit the bacterial survival and multiplication [3; 4]. In the plant pathogenic bacteria, the T3 SSs have attracted much attention due to their ability to elicit the hypersensitive response (HR), a plant defense mechanism characterized by rapid cell death, in resistant or non-host plants and induce disease symptoms in host plants [4; 5]. In _Erwinia amylova_, for instance, the T3 SS is a major pathogenicity factor as the T3 SS-deficient mutants are unable to cause fire blight disease in Rosaceous plant hosts [6; 7]. Studies of the T3 SS from _Pseudomonas syringae_ pv. _tomato_ DC3000, which causes bacterial speck of tomato and the model plant _Arabidopsis thaliana_, have provided valuable informationfor the understanding of host-microbe interactions by signifying the T3 SS and its effectors as essential players involved in the repression of plant defense mechanisms during the bacterial infection [8; 9; 10].  
As is the case for many T3 SS-expressing pathogens, a growing number of studies have explored novel disease management strategies using the T3 SS as a target for the inhibition of bacterial pathogenesis [11; 12; 13]. In the studies of plant pathogenic bacteria, small molecules that target and inhibit the T3 SSs have been discovered. The soft rot plant pathogen _Dickeya dadantii_ served as the model organism due to its well-characterized regulatory pathways of the T3 SS. It has been well established that the T3 SSs from plant pathogenic bacteria are encoded by the hypersensitive response and pathogenicity (_hrp_) operon [14]. Based on the similarities of operon organization and regulatory systems, plant pathogenic bacterial _hrp_ gene clusters are divided into two groups [15; 16]. The group I _hrp_ gene cluster includes those of _P. syringae_, _E. amylovora_, and _Dickeya_ spp., in which the alternative sigma factor HrpL is the master regulator that activates the expression of most _hrp_ genes [17; 18; 19]. _Ralstonia_ spp. and _Xanthomonas_ spp. possess the group II _hrp_ gene clusters, whose expression is heavily relied on an AraC-type transcriptional activator HrpX [20; 21]. Genetic and molecular analyses have identified multiple important regulators that control the expression of T3 SS in plant pathogenic bacteria, suggesting that the regulation of T3 SS is a highly modulated process during the infection of plants by pathogens, and such regulation often occurs in a hierarchical manner.  
In this review, we summarize our current understanding of the regulation of T3 SS, focusing on bacterial second messengers, transcriptional regulators, and post-transcriptional regulators that control the T3 SS in a model pathogen _D. dadantii_. Similar studies of T3 SSs from other plant pathogens, such as _P. syringae_ and _E. amylovora_, have been thoroughly reviewed elsewhere [22; 23; 24; 25; 26]. Furthermore, we discuss early innovations of the T3 SS inhibitors and their modes of action in _D. dadantii_ and _E. amylovora_, highlight the recent discovery of novel T3 SS inhibitors in rice pathogen _X. oryzae_ pv. _oryzae_, bacterial wilt pathogen _R. solanacearum_, and _P. syringae_ pv. _tomato_, and provide remaining challenges and future perspectives on the application of T3 SS inhibitors for managing plant diseases.