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Notably, methicillin\u2010resistant <jats:italic>Staphylococcus aureus<\/jats:italic> (MRSA) and vancomycin\u2010resistant <jats:italic>Enterococcus faecalis<\/jats:italic> (VREF) are designated as serious threats, whereas <jats:italic>Clostridioides difficile<\/jats:italic> (<jats:italic>C. difficile<\/jats:italic>) is recognized as one of the most urgent threats to human health and unmet medical need. Herein, they report the design and application of novel biodegradable \npolymers \u2014 the lipidated antimicrobial guanidinylate polycarbonates. These polymers showed potent antimicrobial activity against a panel of bacteria with fast\u2010killing kinetics and low resistance development tendency, mainly due to their bacterial membrane disruption mechanism. More importantly, the optimal polymer showed excellent antibacterial activity against <jats:italic>C. difficile<\/jats:italic> infection (CDI) in vivo via oral administration. In addition, compared with vancomycin, the polymer demonstrated a much\u2010prolonged therapeutic effect and virtually diminished recurrence rate of CDI. The convenient synthesis, easy scale\u2010up, low cost, as well as biodegradability of this class of polycarbonates, together with their in vitro broad\u2010spectrum antimicrobial activity and orally in vivo efficacy against CDI, suggest the great potential of lipidated guandinylate polycarbonates as a new class of antibacterial biomaterials to treat CDI and combat emerging antibiotic resistance.<\/jats:p>","DOI":"10.1002\/adhm.202303295","type":"journal-article","created":{"date-parts":[[2024,2,7]],"date-time":"2024-02-07T04:24:36Z","timestamp":1707279876000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Antimicrobial Guanidinylate Polycarbonates Show Oral In Vivo Efficacy Against <i>Clostridioides Difficile<\/i>"],"prefix":"10.1002","volume":"13","author":[{"given":"Menglin","family":"Xue","sequence":"first","affiliation":[{"name":"Department of Chemistry University of South Florida  4202 E. Fowler Ave. Tampa FL 33620 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soumyadeep","family":"Chakraborty","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Morsani College of Medicine University of South Florida  12901 Bruce B Downs Blvd Tampa FL 33612 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruixuan","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of South Florida  4202 E. 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Fowler Ave. Tampa FL 33620 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanhai","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Science Taneja College of Pharmacy University of South Florida  Tampa FL 33612 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingmin","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Morsani College of Medicine University of South Florida  12901 Bruce B Downs Blvd Tampa FL 33612 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3106-3306","authenticated-orcid":false,"given":"Jianfeng","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of South Florida  4202 E. 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