{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T04:13:34Z","timestamp":1792728814832,"version":"4.5.0"},"reference-count":64,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"801","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2025,6,4]]},"abstract":"<jats:p>The high mortality of drug-resistant Gram-negative bacterial infections and the scarcity of antibiotics against Gram-negative bacteria urgently call for effective antimicrobial agents. Antimicrobial polymers that mimic host defense peptides (HDPs) have been extensively studied, but in the complex in vivo environment, cationic polymers can interact with polyanionic macromolecules and host cells bearing polyanionic membranes, leading to undesired side effects. Here, we report an \u201cacid-responsive antimicrobial polymer prodrug\u201d strategy and performed a proof-of-concept treatment using HDP-mimicking poly(2-oxazoline)s. By protecting the side-chain amines with 2,3-dimethylmaleic anhydride to neutralize the positive charges, the poly(2-oxazoline) prodrug can remain stealthy under physiological conditions but expose these charges to become activated at infection sites. The poly(2-oxazoline) prodrug exhibited high biocompatibility, prolonged blood circulation time, and potent activity against drug-resistant Gram-negative bacteria and biofilms in vitro and did not develop antibacterial resistance. Moreover, the poly(2-oxazoline) prodrug showed strong therapeutic potential for both local and systemic infections. The prodrug displayed potent activity in treating Gram-negative bacteria\u2013associated infections in multiple mouse models, including subcutaneous abscess, neutropenic thigh infection, kidney infection, lung infection, and peritonitis. These results demonstrate the effectiveness of our prodrug strategy to develop potent antibacterial agents.<\/jats:p>","DOI":"10.1126\/scitranslmed.adl4870","type":"journal-article","created":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T13:58:46Z","timestamp":1749045526000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":32,"title":["A host defense peptide\u2013mimicking prodrug activated by drug-resistant Gram-negative bacterial infections"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3399-0894","authenticated-orcid":true,"given":"Jiayang","family":"Xie","sequence":"first","affiliation":[{"name":"State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0444-0324","authenticated-orcid":true,"given":"Min","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3462-7373","authenticated-orcid":true,"given":"Zihao","family":"Cong","sequence":"additional","affiliation":[{"name":"Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Key Laboratory for Ultrafine Materials of Ministry of Education, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Engineering Research Center for Biomedical Materials of Ministry of Education, Key Laboratory of Specially Functional Polymeric Materials and Related Technology (Ministry of Education), School of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7096-8784","authenticated-orcid":true,"given":"Ximian","family":"Xiao","sequence":"additional","affiliation":[{"name":"Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Key Laboratory for Ultrafine Materials of Ministry of Education, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Engineering Research Center for Biomedical Materials of Ministry of Education, Key Laboratory of Specially Functional Polymeric Materials and Related Technology (Ministry of Education), School of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longqiang","family":"Liu","sequence":"additional","affiliation":[{"name":"Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Key Laboratory for Ultrafine Materials of Ministry of Education, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Engineering Research Center for Biomedical Materials of Ministry of Education, Key Laboratory of Specially Functional Polymeric Materials and Related Technology (Ministry of Education), School of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9090-3905","authenticated-orcid":true,"given":"Sheng","family":"Chen","sequence":"additional","affiliation":[{"name":"Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Key Laboratory for Ultrafine Materials of Ministry of Education, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Engineering Research Center for Biomedical Materials of Ministry of Education, Key Laboratory of Specially Functional Polymeric Materials and Related Technology (Ministry of Education), School of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5393-5713","authenticated-orcid":true,"given":"Weinan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou 215163, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7668-7409","authenticated-orcid":true,"given":"Yueming","family":"Wu","sequence":"additional","affiliation":[{"name":"Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Key Laboratory for Ultrafine Materials of Ministry of Education, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Engineering Research Center for Biomedical Materials of Ministry of Education, Key Laboratory of Specially Functional Polymeric Materials and Related Technology (Ministry of Education), School of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7699-086X","authenticated-orcid":true,"given":"Runhui","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China."},{"name":"Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Key Laboratory for Ultrafine Materials of Ministry of Education, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Engineering Research Center for Biomedical Materials of Ministry of Education, Key Laboratory of Specially Functional Polymeric Materials and Related Technology (Ministry of Education), School of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237, China."},{"name":"Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou 215163, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3009315"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature.2017.21550"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1086\/595011"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/499394a"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13756-018-0404-3"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4572"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-micro-102215-095308"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1665-6"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2201-c1"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.02.056"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41570-021-00313-1"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/415389a"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1267"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-019-0058-8"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd1133"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.12.4673-4679.2004"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja045664d"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja044205"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmat2915"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms3861"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja077288d"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja500367u"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201311150"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1507893112"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.accounts.5b00492"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biomac.6b01057"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.7b12140"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/adma.201805092"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1039\/D0BM01211D"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-26221-y"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.1c02324"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202104402"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2006.04.014"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1002\/adma.201202296"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.6b00843"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2018.07.017"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1821410116"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202000505"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202200778"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1021\/acsnano.0c00269"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202006772"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1021\/acsbiomaterials.7b00723"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biomac.9b00392"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202101244"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1039\/C7OB02188G"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd1008"},{"key":"e_1_3_2_48_2","first-page":"267","article-title":"Persister cells and the riddle of biofilm survival","volume":"70","author":"Lewis K.","year":"2005","unstructured":"K. Lewis, Persister cells and the riddle of biofilm survival. Biochemistry 70, 267\u2013274 (2005).","journal-title":"Biochemistry"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf4268"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1401876111"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1417703112"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abn0771"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.2c01583"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202301664"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.6b01435"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-02875-z"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-020-0723-z"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201601621"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03899-0"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmicrobiol.2016.162"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aax1946"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1021\/ma200426y"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja207150n"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2018.01724"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics9080506"}],"container-title":["Science Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scitranslmed.adl4870","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T13:58:54Z","timestamp":1749045534000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adl4870"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,4]]},"references-count":64,"journal-issue":{"issue":"801","published-print":{"date-parts":[[2025,6,4]]}},"alternative-id":["10.1126\/scitranslmed.adl4870"],"URL":"https:\/\/doi.org\/10.1126\/scitranslmed.adl4870","relation":{},"ISSN":["1946-6234","1946-6242"],"issn-type":[{"value":"1946-6234","type":"print"},{"value":"1946-6242","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,4]]},"assertion":[{"value":"2023-10-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-07-29","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-13","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-04","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadl4870"}}