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Bortezomib Eliminates Persistent Chlamydia trachomatis Infection through Rapid and Specific Host Cell Apoptosis
Ryota Itoh1, Yusuke Kurihara1, Michinobu Yoshimura1
1Department of Microbiology & Immunology, Faculty of Medicine, Fukuoka University, Fukuoka 814-0180, Japan.
Abstract:
Chlamydia trachomatis, a parasitic intracellular bacterium, is a major human pathogen that causes millions of trachoma, sexually transmitted infections, and pneumonia cases worldwide. Previously, peptidomimetic inhibitors consisting of a hydrophobic dipeptide derivative exhibited significant inhibitory effects against chlamydial growth. Based on this finding, this study showed that both bortezomib (BTZ) and ixazomib (IXA), anticancer drugs characterized by proteasome inhibitors, have intensive inhibitory activity against Chlamydia. Both BTZ and IXA consisted of hydrophobic dipeptide derivatives and strongly restricted the growth of Chlamydia (BTZ, IC50 = 24 nM). In contrast, no growth inhibitory effect was observed for other nonintracellular parasitic bacteria, such as Escherichia coli. BTZ and IXA appeared to inhibit chlamydial growth bacteriostatically via electron microscopy. Surprisingly, Chlamydia-infected cells that induced a persistent infection state were selectively eliminated by BTZ treatment, whereas uninfected cells survived. These results strongly suggested the potential of boron compounds based on hydrophobic dipeptides for treating chlamydial infections, including persistent infections, which may be useful for future therapeutic use in chlamydial infectious diseases.
Insights
Bortezomib and ixazomib, proteasome inhibitors, effectively inhibit Chlamydia trachomatis growth. These compounds also selectively eliminate infected cells, suggesting potential for treating persistent chlamydial infections.
Area of Science:
- Microbiology
- Infectious Diseases
- Drug Discovery
Background:
- Chlamydia trachomatis is a significant human pathogen causing trachoma, STIs, and pneumonia.
- Previous research identified peptidomimetic inhibitors with hydrophobic dipeptide derivatives effective against chlamydial growth.
Purpose of the Study:
- To investigate the inhibitory activity of bortezomib (BTZ) and ixazomib (IXA) against Chlamydia.
- To explore the therapeutic potential of these compounds, particularly in persistent infections.
Main Methods:
- Testing BTZ and IXA, known proteasome inhibitors and hydrophobic dipeptide derivatives, for activity against Chlamydia.
- Utilizing electron microscopy to observe the mechanism of growth inhibition.
- Assessing the effect of BTZ on Chlamydia-infected cells versus uninfected cells.
Main Results:
- BTZ and IXA demonstrated potent inhibitory activity against Chlamydia growth (BTZ, IC50 = 24 nM).
- No significant inhibition was observed against non-intracellular bacteria like Escherichia coli.
- BTZ selectively eliminated Chlamydia-infected cells, sparing uninfected cells, suggesting a mechanism for clearing persistent infections.
Conclusions:
- Boron compounds based on hydrophobic dipeptides, like BTZ and IXA, show promise for treating chlamydial infections.
- These compounds may be particularly useful for addressing persistent and difficult-to-treat chlamydial diseases.
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