{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T04:49:17Z","timestamp":1775710157925,"version":"3.50.1"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T00:00:00Z","timestamp":1775692800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>\n                    The increasing antimicrobial resistance of\n                    <jats:italic>Streptococcus pneumoniae<\/jats:italic>\n                    (\n                    <jats:italic>S. pneumoniae<\/jats:italic>\n                    ) presents a major therapeutic challenge and underscores the need for agents with novel mechanisms of action. Azeliragon is a small-molecule inhibitor of the receptor for advanced glycation end products (RAGE), but its antibacterial activity has not been well defined. In this study, we systematically evaluated the\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    anti-infective effects of azeliragon against\n                    <jats:italic>S. pneumoniae<\/jats:italic>\n                    . Azeliragon exhibited minimum inhibitory concentration (MIC) values predominantly ranging from 4 to 8\u202f\u03bcg\/mL, with MIC\u2085\u2080 and MIC\u2089\u2080 values of 4\u202f\u03bcg\/mL and 8\u202f\u03bcg\/mL against clinical isolates, respectively. Growth-curve and time-kill assays demonstrated concentration- and time-dependent antibacterial activity, resulting in a marked reduction in viable bacteria within 6\u20138\u202fh at 4\u00d7 MIC. Azeliragon also significantly reduced the biomass of mature\n                    <jats:italic>S. pneumoniae<\/jats:italic>\n                    biofilms. Mechanistic analyses showed that azeliragon disrupted bacterial membrane integrity and increased intracellular reactive oxygen species levels, indicating that membrane damage and enhanced oxidative stress contribute to its bactericidal effect.\n                    <jats:italic>in vivo<\/jats:italic>\n                    , azeliragon conferred significant protection in a mouse infection model of\n                    <jats:italic>S. pneumoniae<\/jats:italic>\n                    , improving survival to approximately 60\u201370%. In a non-lethal infection model, azeliragon markedly reduced bacterial loads in blood and lung tissues and significantly decreased serum levels of pro-inflammatory cytokines, including TNF-\u03b1 and IL-6. Collectively, these findings provide the first systematic evidence that the RAGE inhibitor azeliragon exerts direct anti-\n                    <jats:italic>S. pneumoniae<\/jats:italic>\n                    activity and affords\n                    <jats:italic>in vivo<\/jats:italic>\n                    protection, supporting its potential as a novel antibacterial candidate for pneumococcal infections.\n                  <\/jats:p>","DOI":"10.3389\/fmed.2026.1793580","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T04:10:49Z","timestamp":1775707849000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Protective effects of the RAGE inhibitor azeliragon as a potential anti-Streptococcus pneumoniae therapeutic in sepsis models"],"prefix":"10.3389","volume":"13","author":[{"given":"Lei","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Tongxiang First People\u2019s Hospital","place":["Jiaxing, Zhejiang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao","family":"Lu","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Heze University","place":["Heze, Shandong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Tongxiang First People\u2019s Hospital","place":["Jiaxing, Zhejiang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,9]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1128\/microbiolspec.gpp3-0004-2018","article-title":"Streptococcus pneumoniae: invasion and inflammation","volume":"7","author":"Loughran","year":"2019","journal-title":"Microbiol 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