Type III secretion system ATPase and flagellar export ATPase (SctN/FliI)

The Type III secretion system (T3SS) ATPase and its homologous flagellar export ATPase are essential molecular motors in Gram-negative bacteria [7, 18]. These enzymes, often referred to as SctN and FliI respectively, belong to the AAA+ ATPase family and are located at the base of the T3SS injectisome or flagellar apparatus [5, 18]. Their primary biological function is to provide the energy required for the unfolding and translocation of effector proteins or flagellar subunits into the secretion channel [7, 13, 18]. By hydrolyzing ATP, these ATPases facilitate the dissociation of chaperone-effector complexes, which is a prerequisite for the delivery of virulence factors into host cells [7, 19, 20]. In the context of disease, these proteins are critical for the pathogenicity of various bacteria, including Salmonella, Shigella, Yersinia, and Pseudomonas [11, 12, 16, 18]. Because they are essential for virulence and motility but not for bacterial viability, they are considered high-priority targets for the development of antivirulence drugs [11, 12, 21, 25]. Small molecule inhibitors targeting these ATPases aim to "disarm" the pathogen, preventing the injection of toxins and reducing the severity of infection [1, 11, 12]. This approach offers a potential alternative to traditional antibiotics, as it may reduce the selective pressure that drives the emergence of multi-drug resistance [11, 21, 25]. Research has identified several experimental inhibitors, such as salicylidene acylhydrazides and hydroxyquinoline derivatives, which demonstrate the feasibility of targeting these enzymes [12, 21, 25]. However, achieving high selectivity to avoid inhibiting host ATPases remains a significant challenge in the development of these therapeutic agents [1, 11].

Other names

SctNFliIEscNSpa47InvCSsaNYscNHrpB6VscNType 3 secretion system ATPaseFlagellar protein export ATPaseInjectisome ATPase

Inhibition of ATPase activity, blocking of effector protein unfolding and translocation, and prevention of T3SS assembly.