{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T21:26:11Z","timestamp":1792099571699,"version":"4.4.0"},"reference-count":45,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T00:00:00Z","timestamp":1747872000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T00:00:00Z","timestamp":1747872000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Bacteriol"],"published-print":{"date-parts":[[2025,5,22]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:sec>\n            <jats:title\/>\n            <jats:p>\n              Antibiotic combinations can slow down resistance development and\/or achieve synergistic therapeutic effects. In this study, we observed that a combined use of ceftazidime-avibactam (CZA) with azithromycin effectively repressed CZA resistance development in\n              <jats:italic toggle=\"yes\">Pseudomonas aeruginosa<\/jats:italic>\n              . Transcriptome analysis revealed that subinhibitory concentrations of azithromycin reduced the expression of genes involved in stress-induced mutagenesis, including the stress response sigma factor\n              <jats:italic toggle=\"yes\">rpoS<\/jats:italic>\n              . Interestingly, ribosome profiling revealed global redistribution of ribosomes by azithromycin, among which ribosome stalling was significantly intensified near the 5\u00b4 terminus of the\n              <jats:italic toggle=\"yes\">rpoS<\/jats:italic>\n              mRNA. Further DNA mutational analysis revealed that azithromycin represses the translation of\n              <jats:italic toggle=\"yes\">rpoS<\/jats:italic>\n              through its 5\u00b4-terminal rare codons, which in turn reduced its transcription. These\n              <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n              observations have been recapitulated\n              <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n              where azithromycin-repressed CZA resistance development when\n              <jats:italic toggle=\"yes\">P. aeruginosa<\/jats:italic>\n              was passaged in mice. Overall, our study revealed the molecular mechanism of azithromycin-mediated repression of antibiotic resistance development, providing a promising antibiotic combination for the treatment of\n              <jats:italic toggle=\"yes\">P. aeruginosa<\/jats:italic>\n              infections.\n            <\/jats:p>\n            <jats:sec>\n              <jats:title>IMPORTANCE<\/jats:title>\n              <jats:p>\n                Antibiotic resistance, a global public health challenge, demands the development of novel antibiotics and therapeutic strategies. Ceftazidime-avibactam (CZA) is a combination of a \u03b2-lactam antibiotic with a \u03b2-lactamase inhibitor that is effective against various gram-negative bacteria such as\n                <jats:italic toggle=\"yes\">Pseudomonas aeruginosa<\/jats:italic>\n                . However, clinical CZA-resistant isolates have been reported. Here, we found that combining CZA with azithromycin can effectively suppress the development of resistance in\n                <jats:italic toggle=\"yes\">P. aeruginosa in vitro<\/jats:italic>\n                and\n                <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                . Moreover, we found that azithromycin represses the translation initiation of\n                <jats:italic toggle=\"yes\">rpoS<\/jats:italic>\n                through its 5\u00b4-terminal rare and less frequent codons, thereby subsequently reducing the mutational frequency of CZA resistance. Therefore, our work provides a promising antibiotic combination for the treatment of\n                <jats:italic toggle=\"yes\">P. aeruginosa<\/jats:italic>\n                infections.\n              <\/jats:p>\n            <\/jats:sec>\n          <\/jats:sec>","DOI":"10.1128\/jb.00552-24","type":"journal-article","created":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T01:08:11Z","timestamp":1746061691000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":5,"title":["Azithromycin represses evolution of ceftazidime\/avibactam resistance by translational repression of\n            <i>rpoS<\/i>\n            in\n            <i>Pseudomonas aeruginosa<\/i>"],"prefix":"10.1128","volume":"207","author":[{"given":"Congjuan","family":"Xu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Molecular Microbiology and Technology of the Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Feng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Molecular Microbiology and Technology of the Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuchen","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Molecular Microbiology and Technology of the Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Ren","sequence":"additional","affiliation":[{"name":"State Key Laboratory 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