{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T21:09:13Z","timestamp":1790629753730,"version":"4.1.0"},"reference-count":31,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2022,7,4]],"date-time":"2022-07-04T00:00:00Z","timestamp":1656892800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science","award":["19K16659"],"award-info":[{"award-number":["19K16659"]}]},{"name":"Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science","award":["JP21K16329"],"award-info":[{"award-number":["JP21K16329"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms23137434","type":"journal-article","created":{"date-parts":[[2022,7,4]],"date-time":"2022-07-04T11:15:05Z","timestamp":1656933305000},"page":"7434","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Bortezomib Eliminates Persistent Chlamydia trachomatis Infection through Rapid and Specific Host Cell Apoptosis"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9487-5566","authenticated-orcid":false,"given":"Ryota","family":"Itoh","sequence":"first","affiliation":[{"name":"Department of Microbiology & Immunology, Faculty of Medicine, Fukuoka University, Fukuoka 814-0180, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Kurihara","sequence":"additional","affiliation":[{"name":"Department of Microbiology & Immunology, Faculty of Medicine, Fukuoka University, Fukuoka 814-0180, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michinobu","family":"Yoshimura","sequence":"additional","affiliation":[{"name":"Department of Microbiology & Immunology, Faculty of Medicine, Fukuoka University, Fukuoka 814-0180, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3496-6087","authenticated-orcid":false,"given":"Kenji","family":"Hiromatsu","sequence":"additional","affiliation":[{"name":"Department of Microbiology & Immunology, Faculty of Medicine, Fukuoka University, Fukuoka 814-0180, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"a010256","DOI":"10.1101\/cshperspect.a010256","article-title":"Chlamydial Intracellular Survival Strategies","volume":"3","author":"Bastidas","year":"2013","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1038\/nrmicro.2016.30","article-title":"Chlamydia cell biology and pathogenesis","volume":"14","author":"Elwell","year":"2016","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_3","first-page":"1411","article-title":"Diagnosis and treatment of Chlamydia trachomatis infection","volume":"73","author":"Miller","year":"2006","journal-title":"Am. Fam. Physician"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Prohl, A., Lohr, M., Ostermann, C., Liebler-Tenorio, E., Berndt, A., Schroedl, W., Rothe, M., Schubert, E., Sachse, K., and Reinhold, P. (2015). Enrofloxacin and Macrolides Alone or in Combination with Rifampicin as Antimicrobial Treatment in a Bovine Model of Acute Chlamydia psittaci Infection. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0119736"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Hocking, J.S., Vodstrcil, L.A., Huston, W.M., Timms, P., Chen, M.Y., Worthington, K., McIver, R., Tabrizi, S.N., and Australian Chlamydia Treatment, S. (2013). A cohort study of Chlamydia trachomatis treatment failure in women: A study protocol. BMC Infect. Dis., 13.","DOI":"10.1186\/1471-2334-13-379"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1093\/jac\/dku493","article-title":"Treatment of rectal chlamydia infection may be more complicated than we originally thought","volume":"70","author":"Hocking","year":"2015","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e00203-17","DOI":"10.1128\/CVI.00203-17","article-title":"Chlamydia trachomatis: The Persistent Pathogen","volume":"24","author":"Witkin","year":"2017","journal-title":"Clin. Vaccine Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3101","DOI":"10.3389\/fmicb.2018.03101","article-title":"Chlamydia Persistence: A Survival Strategy to Evade Antimicrobial Effects in-vitro and in-vivo","volume":"9","author":"Panzetta","year":"2018","journal-title":"Front. Microbiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"S88","DOI":"10.1086\/652394","article-title":"Chlamydia trachomatis Persistence In Vitro: An Overview","volume":"201","author":"Wyrick","year":"2010","journal-title":"J. Infect. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/82_2016_15","article-title":"Chlamydia trachomatis as the Cause of Infectious Infertility: Acute, Repetitive or Persistent Long-Term Infection?","volume":"412","author":"Schuchardt","year":"2018","journal-title":"Biol. Chlamydia"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1086\/315372","article-title":"Multiple drug-resistant Chlamydia trachomatis associated with clinical treatment failure","volume":"181","author":"Somani","year":"2000","journal-title":"J. Infect. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1016\/j.jiac.2019.05.024","article-title":"Anti-chlamydial activities of cell-permeable hydrophobic dipeptide-containing derivatives","volume":"25","author":"Itoh","year":"2019","journal-title":"J. Infect. Chemother."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1002\/ajh.23358","article-title":"Good clinical activity and favorable toxicity profile of once weekly bortezomib, fotemustine, and dexamethasone (B-MuD) for the treatment of relapsed multiple myeloma","volume":"88","author":"Mangiacavalli","year":"2013","journal-title":"Am. J. Hematol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2173","DOI":"10.1002\/cam4.4313","article-title":"Ixazomib-based maintenance therapy after bortezomib-based induction in patients with multiple myeloma not undergoing transplantation: A real-world study","volume":"11","author":"Shen","year":"2022","journal-title":"Cancer Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e04287","DOI":"10.1002\/ccr3.4287","article-title":"Successful ixazomib treatment for relapsed and refractory acute myeloid leukemia transformed from myelodysplastic syndrome","volume":"9","author":"Oka","year":"2021","journal-title":"Clin. Case Rep."},{"key":"ref_16","first-page":"2875","article-title":"Endoplasmic reticulum stress triggers delanzomib-induced apoptosis in HCC cells through the PERK\/eIF2 alpha\/ATF4\/CHOP pathway","volume":"12","author":"Li","year":"2020","journal-title":"Am. J. Transl. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.ejca.2012.09.009","article-title":"A first in human phase I study of the proteasome inhibitor CEP-18770 in patients with advanced solid tumours and multiple myeloma","volume":"49","author":"Gallerani","year":"2013","journal-title":"Eur. J. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2487","DOI":"10.1056\/NEJMoa043445","article-title":"Bortezomib or high-dose dexamethasone for relapsed multiple myeloma","volume":"352","author":"Richardson","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.str.2005.11.019","article-title":"Crystal structure of the boronic acid-based proteasome inhibitor bortezomib in complex with the yeast 20S proteasome","volume":"14","author":"Groll","year":"2006","journal-title":"Structure"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e02260-17","DOI":"10.1128\/AAC.02260-17","article-title":"Pyocyanin Inhibits Chlamydia Infection by Disabling Infectivity of the Elementary Body and Disrupting Intracellular Growth","volume":"62","author":"Li","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e00253-15","DOI":"10.1128\/mBio.00253-15","article-title":"Target Mechanism-Based Whole-Cell Screening Identifies Bortezomib as an Inhibitor of Caseinolytic Protease in Mycobacteria","volume":"6","author":"Moreira","year":"2015","journal-title":"MBio"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1016\/j.resmic.2004.06.003","article-title":"Comparative genomics and functional roles of the ATP-dependent proteases Lon and Clp during cytosolic protein degradation","volume":"155","author":"Chandu","year":"2004","journal-title":"Res. Microbiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/0076-6879(94)44027-1","article-title":"Atp-Dependent Protease La (Lon) from Escherichia-Coli","volume":"244","author":"Goldberg","year":"1994","journal-title":"Proteolytic Enzym. Serine Cysteine Pept."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/0076-6879(94)44025-5","article-title":"Endopeptidase-Clp\u2014Atp-Dependent Clp Protease from Escherichia-Coli","volume":"244","author":"Maurizi","year":"1994","journal-title":"Proteolytic Enzym. Serine Cysteine Pept."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e02016-20","DOI":"10.1128\/mBio.02016-20","article-title":"The ClpX and ClpP2 Orthologs of Chlamydia trachomatis Perform Discrete and Essential Functions in Organism Growth and Development","volume":"11","author":"Wood","year":"2020","journal-title":"MBio"},{"key":"ref_26","first-page":"e00635-18","article-title":"Initial Characterization of the Two ClpP Paralogs of Chlamydia trachomatis Suggests Unique Functionality for Each","volume":"201","author":"Wood","year":"2019","journal-title":"J. Bacteriol."},{"key":"ref_27","first-page":"217","article-title":"Spotlight on ixazomib: Potential in the treatment of multiple myeloma","volume":"10","author":"Muz","year":"2016","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1970","DOI":"10.1158\/0008-5472.CAN-09-2766","article-title":"Evaluation of the Proteasome Inhibitor MLN9708 in Preclinical Models of Human Cancer","volume":"70","author":"Kupperman","year":"2010","journal-title":"Cancer Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2442","DOI":"10.1128\/IAI.69.4.2442-2447.2001","article-title":"Persistent Chlamydia trachomatis infections resist apoptotic stimuli","volume":"69","author":"Dean","year":"2001","journal-title":"Infect. Immun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nrd.2018.168","article-title":"Drug repurposing: Progress, challenges and recommendations","volume":"18","author":"Pushpakom","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/j.bbrc.2014.08.128","article-title":"Chlamydia pneumoniae harness host NLRP3 inflammasome-mediated caspase-1 activation for optimal intracellular growth in murine macrophages","volume":"452","author":"Itoh","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/13\/7434\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:42:34Z","timestamp":1760139754000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/13\/7434"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,4]]},"references-count":31,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["ijms23137434"],"URL":"https:\/\/doi.org\/10.3390\/ijms23137434","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,4]]}}}