Various antibacterial agents have been developed and used for the treatment and prevention of infectious diseases. These drugs show antibacterial activity by inhibiting growth or directly killing bacteria. This antibacterial activity induces the microbial substitution and the emergence of drug-resistant bacteria.1) Therefore, improper use of antibacterial agents selects for drug-resistant bacteria and increases their prevalence. To prevent this problem, it is necessary to develop therapeutic agents that are fundamentally different from current antibacterial agents.2) It is possible that prevention or blockage of bacterial infections could be achieved by interfering with the adherence and/or the invasion of bacteria in host cells. The type III secretion apparatus, one of the virulence factors in bacteria, is necessary for the invasion of pathogenic bacteria into host cells. [3][4][5] Preventing the function of the type III secretion apparatus can attenuate the infectious capacity of pathogenic bacteria, including Yersinia 6) and Chlamydia, 7) without actually killing of the bacteria. Therefore, the type III apparatus has been considered a candidate target site for the development of new antibacterial agents. 8,9) Actin-like protein, MreB, which serves a cytoskeletal function, is necessary for maintenance of the rod-shape of bacteria, including Escherichia coli and Bacillus subtilis. [10][11][12] Furthermore, MreB is associated with chromosome segregation and protein localization to the cell poles.13-15) S-(3,4-Dichlorobenzyl)isothiourea (A22), which was discovered as an inhibitor of replication in E. coli, inhibits the function of MreB by binding to MreB and transforming rod-shaped bacterial cells into coccoid forms. 13,16) A22 has a bacteriostatic effect on certain Gram-negative bacilli, including E. coli.
16)Shigella spp., which are Gram-negative rod-shaped bacteria, are some of the causative agents of bacillary dysentery.
17)Via oral ingestion, Shigella reaches the colon and invades the intestinal epithelial cells, causing destruction of the epithelial layer. The type III secretion system is necessary for the invasion of Shigella into epithelial cells and it delivers effectors directly into host cells. 17,18) The secreted effectors identified in S. flexneri are virulence factors for host cells and various type III effectors, including IpaA, IpaB, IpaC, IpaD, IpgD, and VirA. [18][19][20] Type III secretion systems are not found in non-pathogens. Furthermore, in addition to the type III secretion system, the rod-shape of Shigella seems likely to be necessary for the invasion of host cells because the shape of the cells is linked to the polar localization of certain proteins, including IcsA. 15,21) In this study, the antibacterial activity of A22 was determined, in addition to its coccoid form-inducing effects. Furthermore, the infectious capacity and effector secretion of A22-induced coccoid Shigella cells were examined. We suggest the utility of A22 as a lead compound for generating new anti-infectious drugs an...