A small-molecule inhibitor of type III secretion inhibits different stages of the infectious cycle of
            <i>Chlamydia trachomatis</i>

Muschiol, Sandra; Bailey, Leslie; Gylfe, Åsa; Sundin, Charlotta; Hultenby, Kjell; Bergström, Sven; Elofsson, Mikael; Wolf‐Watz, Hans; Normark, Staffan; Henriques‐Normark, Birgitta

doi:10.1073/pnas.0606412103

Cited by 174 publications

(168 citation statements)

References 28 publications

Supporting

Mentioning

155

Contrasting

Unclassified

Order By: Relevance

“…The NMR spectra were measured on a Varian XL-400 spectrometer or a Varian Inova 600 spectrometer (Varian, Palo Alto, CA, USA) with 1 H NMR at 400 or 600 MHz, and 13 …”

Section: Identification Of Aurodox and Factumycinmentioning

confidence: 99%

A small-molecule inhibitor of the bacterial type III secretion system protects against in vivo infection with Citrobacter rodentium

et al. 2010

View full text Add to dashboard Cite

The type III secretion system (T3SS) is highly conserved in many Gram-negative pathogenic bacteria and functions as an injector of bacterial proteins (effectors) into host cells. T3SSs are involved in establishing disease processes, but this machinery is not essential for bacterial growth or homeostasis. Thus, T3SS is expected to be a candidate therapeutic target, and inhibitors of T3SSs could potentially reduce virulence without causing bacterial death, thereby avoiding any subsequent development of resistance. We identified a linear polyketide compound, aurodox, as a specific T3SS inhibitor from the culture broth of Streptomyces sp. using a screening system for the T3SS-mediated hemolysis of enteropathogenic Escherichia coli (EPEC) established by our group. Aurodox strongly inhibited T3SS-mediated hemolysis with an IC 50 value of 1.5 lg ml À1 without affecting bacterial growth in liquid media. We also demonstrated that aurodox specifically inhibits the secretion of type IIIsecreted proteins such as EspB, EspF and Map, without affecting the expression of the housekeeping protein GroEL. Furthermore, an in vivo infection study using mice clearly indicated that the administration of aurodox allowed the mice to survive a lethal dose of Citrobactor rodentium, a model bacterium for human pathogens such as EPEC. Thus, our in vivo study directly demonstrated for the first time that this putative T3SS inhibitor can be applied as a novel class of anti-infective agents.

show abstract

“…The NMR spectra were measured on a Varian XL-400 spectrometer or a Varian Inova 600 spectrometer (Varian, Palo Alto, CA, USA) with 1 H NMR at 400 or 600 MHz, and 13 …”

Section: Identification Of Aurodox and Factumycinmentioning

confidence: 99%

A small-molecule inhibitor of the bacterial type III secretion system protects against in vivo infection with Citrobacter rodentium

et al. 2010

View full text Add to dashboard Cite

show abstract

“…These efforts have laid the groundwork for a new class of antibiotics that target regulation of these virulence mechanisms. Several recent reports have described the identification of many such drugs, including inhibitors of type III secretion, quorum sensing, and toxin activity (1)(2)(3)(4)(5)(6)(7).…”

mentioning

confidence: 99%

Virstatin inhibits dimerization of the transcriptional activator ToxT

Shakhnovich

Hung

Pierson

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

117

129

View full text Add to dashboard Cite

The development of antimicrobials is critical in this time of increasing antibiotic resistance of most clinically relevant bacteria. To date, all current antibiotics focus on inhibiting crucial enzymatic activities of their protein targets (i.e., trimethoprim for dihydrofolate reductase), thus disrupting in vitro essential gene functions. In contrast, we have previously reported the identification of virstatin, a small molecule that inhibits virulence regulation in Vibrio cholerae, thereby preventing intestinal colonization in an infant mouse model for cholera. Virstatin prevents expression of the two major V. cholerae virulence factors, cholera toxin (CT) and the toxin coregulated pilus, by inhibiting the virulence transcriptional activator ToxT. It has previously been described that the N-terminal domain of ToxT has the ability to form homodimers. We now demonstrate that virstatin inhibits ToxT dimerization, thus demonstrating that it further falls into a unique class of inhibitors that works by disrupting protein-protein interactions, particularly homodimerization. Using virstatin, truncation mutants of ToxT, and a virstatin-resistant mutant, we show that dimerization is required for ToxT activation of the ctx promoter. In contrast, ToxT dimerization does not appear to be required at all of the other ToxT-regulated promoters, suggesting multiple mechanisms may exist for its transcriptional activity.antibiotics ͉ cholera ͉ pharmacology ͉ regulation ͉ virulence

show abstract

“…The results presented above agree with data for other T3SS inhibitors, which also caused the formation of smaller inclusions containing only one or a few reticulate bodies. In the presence of a small molecule belonging to a class of acylated hydrazones of salicylic aldehydes known as INP0400, internalized EBs were converted to RBs, but RB multiplication was inhibited in a dose-dependent fashion, resulting in ultimately smaller inclusion bodies containing just one or a few RBs (Muschiol et al, 2006).…”

Section: Resultsmentioning

confidence: 99%

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

Zigangirova

Kost

Didenko

et al. 2016

Journal of Medical Microbiology

View full text Add to dashboard Cite

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.

show abstract

A small-molecule inhibitor of type III secretion inhibits different stages of the infectious cycle of Chlamydia trachomatis

Cited by 174 publications

References 28 publications

A small-molecule inhibitor of the bacterial type III secretion system protects against in vivo infection with Citrobacter rodentium

A small-molecule inhibitor of the bacterial type III secretion system protects against in vivo infection with Citrobacter rodentium

Virstatin inhibits dimerization of the transcriptional activator ToxT

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

Contact Info

Product

Resources

About