A small-molecule compound belonging to a class  of 2,4-disubstituted 1,3,4-thiadiazine-5-ones  inhibits intracellular growth and persistence  of Chlamydia trachomatis.
Chlamydia trachomatis is one of the most common sexually transmitted pathogens in the world and often causes chronic inflammatory diseases that are insensitive to antibiotics. The type 3 secretion system (T3SS) of pathogenic bacteria is a promising target for therapeutic intervention aimed at bacterial virulence and can be an attractive alternative for the treatment of chronic infections. Recently, we have shown that a small-molecule compound belonging to a class of 2,4-disubstituted 1,3,4-thiadiazine-5-ones produced through the chemical modification of the thiohydrazides of oxamic acids, designated CL-55, inhibited the intracellular growth of C. trachomatis in a T3SS-dependent manner. To assess the feasibility of CL-55 as a therapeutic agent, our aim was to determine which point(s) in the developmental cycle CL-55 affects. We found that CL-55 had no effect on the adhesion of elementary bodies (EBs) to host cells but significantly suppressed EB internalization. We further found that CL-55 inhibited the intracellular division of reticulate bodies (RBs). An ultrastructural analysis revealed loss of contact between the RBs and the inclusion membrane in the presence of CL-55. Finally, we found that our T3SS inhibitor prevented the persistence of Chlamydia in cell culture and its reversion to the infectious state. Our findings indicate that our T3SS inhibitor may be effective in the treatment of both productive and persistent infections.
Gamaleya Center of Epidemiology and Microbiology, Ministry of Health Russian Federation, 123098, Gamaleya Str. 18, Moscow, Russian Federation.
Naylia A
NA
Zigangirova
Gamaleya Center of Epidemiology and Microbiology, Ministry of Health Russian Federation, 123098, Gamaleya Str. 18, Moscow, Russian Federation.
Elena A
EA
Kost
Gamaleya Center of Epidemiology and Microbiology, Ministry of Health Russian Federation, 123098, Gamaleya Str. 18, Moscow, Russian Federation.
Lubov V
LV
Didenko
Gamaleya Center of Epidemiology and Microbiology, Ministry of Health Russian Federation, 123098, Gamaleya Str. 18, Moscow, Russian Federation.
Lydia N
LN
Kapotina
Gamaleya Center of Epidemiology and Microbiology, Ministry of Health Russian Federation, 123098, Gamaleya Str. 18, Moscow, Russian Federation.
Egor S
ES
Zayakin
Gamaleya Center of Epidemiology and Microbiology, Ministry of Health Russian Federation, 123098, Gamaleya Str. 18, Moscow, Russian Federation.
Sergei I
SI
Luyksaar
Gamaleya Center of Epidemiology and Microbiology, Ministry of Health Russian Federation, 123098, Gamaleya Str. 18, Moscow, Russian Federation.
Elena Y
EY
Morgunova
Gamaleya Center of Epidemiology and Microbiology, Ministry of Health Russian Federation, 123098, Gamaleya Str. 18, Moscow, Russian Federation.
Elena D
ED
Fedina
Bauman Moscow State Technical University, 105005, 2nd Baumanskaya Str. 5, Moscow, Russian Federation.
Olga A
OA
Artyukhova
Bauman Moscow State Technical University, 105005, 2nd Baumanskaya Str. 5, Moscow, Russian Federation.
Andrey V
AV
Samorodov
Gamaleya Center of Epidemiology and Microbiology, Ministry of Health Russian Federation, 123098, Gamaleya Str. 18, Moscow, Russian Federation.
Natalya V
NV
Kobets
D000818:Animals; D001422:Bacterial Adhesion / Q000187:drug effects; D001426:Bacterial Proteins; D002460:Cell Line; D002692:Chlamydia trachomatis / Q000187:drug effects* / Q000254:growth & development; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008970:Molecular Weight; D010406:Penicillins / Q000494:pharmacology; D013829:Thiadiazines / Q000737:chemistry / Q000494:pharmacology*; D000069296:Type III Secretion Systems / Q000037:antagonists & inhibitors
D001426:Bacterial Proteins; D010406:Penicillins; D013829:Thiadiazines; D000069296:Type III Secretion Systems