{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T14:10:12Z","timestamp":1789135812775,"version":"build-2803163510"},"reference-count":39,"publisher":"American Chemical Society (ACS)","issue":"9","license":[{"start":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T00:00:00Z","timestamp":1787529600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T00:00:00Z","timestamp":1787529600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T00:00:00Z","timestamp":1787529600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Staphylococcus aureus infections pose a serious threat to public health, exacerbated by antimicrobial resistance and the limited pipeline of novel agents. Pleuromutilin, a natural antibiotic, provides a promising scaffold for developing new antibacterial agents via structural modification. To overcome the poor druggability of the lead compound amphenmulin (APM), we designed and synthesized a novel derivative, Pleuro2\u20134. This derivative exhibited potent in vitro activity against S. aureus, with efficacy comparable to valnemulin and superior to tiamulin. Molecular docking suggested favorable interactions with the bacterial ribosome, while scanning electron microscopy revealed morphological alterations associated with impaired cell division. Pharmacokinetics in mice revealed dose-dependent oral bioavailability (21.28% to 70.13%) and rapid metabolism to APM. Pleuro2\u20134 significantly reduced bacterial loads in a dose-dependent manner and alleviated histopathological damage in a neutropenic murine thigh infection model. Collectively, Pleuro2\u20134 exhibited improved oral exposure and bioavailability with potent antibacterial efficacy and favorable pharmacokinetic properties, warranting further pharmacokinetic\/pharmacodynamic and efficacy studies in target species.<\/jats:p>","DOI":"10.1021\/acsinfecdis.6c00558","type":"journal-article","created":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T23:28:54Z","timestamp":1788132534000},"page":"3230-3240","source":"Crossref","is-referenced-by-count":0,"title":["<i>In Vitro<\/i>\n                    and\n                    <i>In Vivo<\/i>\n                    Activity against\n                    <i>Staphylococcus aureus<\/i>\n                    and Pharmacokinetic Evaluation of a Novel Pleuromutilin\nCandidate"],"prefix":"10.1021","volume":"12","author":[{"given":"Feifei","family":"Zhao","sequence":"first","affiliation":[{"name":"South China Agricultural University , , ,","place":["Guangzhou, China, 510642"]},{"name":"South China Agricultural University , , ,","place":["Guangzhou, China, 510642"]},{"name":"South China Agricultural University , , ,","place":["Guangzhou, China, 510642"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyue","family":"Luo","sequence":"additional","affiliation":[{"name":"South China Agricultural University , , ,","place":["Guangzhou, China, 510642"]},{"name":"South China Agricultural University , , ,","place":["Guangzhou, China, 510642"]},{"name":"South China Agricultural University , , ,","place":["Guangzhou, China, 510642"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Zhang","sequence":"additional","affiliation":[{"name":"South China Agricultural University , , ,","place":["Guangzhou, China, 510642"]},{"name":"South China Agricultural University , , ,","place":["Guangzhou, China, 510642"]},{"name":"South China Agricultural University , , ,","place":["Guangzhou, China, 510642"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Honghao","family":"Huang","sequence":"additional","affiliation":[{"name":"South China Agricultural University , , ,","place":["Guangzhou, China, 510642"]},{"name":"South China Agricultural University , , ,","place":["Guangzhou, China, 510642"]},{"name":"South China Agricultural University , , ,","place":["Guangzhou, China, 510642"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yizhen","family":"Zhu","sequence":"additional","affiliation":[{"name":"South China Agricultural University , , ,","place":["Guangzhou, China, 510642"]},{"name":"South China Agricultural University , , ,","place":["Guangzhou, China, 510642"]},{"name":"South China Agricultural University , , ,","place":["Guangzhou, China, 510642"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanxin","family":"Lin","sequence":"additional","affiliation":[{"name":"South China Agricultural University , , ,","place":["Guangzhou, China, 510642"]},{"name":"South China Agricultural University , , ,","place":["Guangzhou, China, 510642"]},{"name":"South China Agricultural University , , ,","place":["Guangzhou, China, 510642"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sujuan","family":"Wu","sequence":"additional","affiliation":[{"name":"South China Agricultural University , , ,","place":["Guangzhou, China, 510642"]},{"name":"South China Agricultural University , , ,","place":["Guangzhou, China, 510642"]},{"name":"South China Agricultural University , , ,","place":["Guangzhou, China, 510642"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2293-0287","authenticated-orcid":true,"given":"Youzhi","family":"Tang","sequence":"additional","affiliation":[{"name":"South China Agricultural University , , ,","place":["Guangzhou, China, 510642"]},{"name":"South China Agricultural University , , ,","place":["Guangzhou, China, 510642"]},{"name":"South China Agricultural University , , ,","place":["Guangzhou, China, 510642"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1103-7170","authenticated-orcid":true,"given":"Zhenling","family":"Zeng","sequence":"additional","affiliation":[{"name":"South China Agricultural University , , ,","place":["Guangzhou, China, 510642"]},{"name":"South China Agricultural University , , ,","place":["Guangzhou, China, 510642"]},{"name":"South China Agricultural University , , ,","place":["Guangzhou, China, 510642"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,24]]},"reference":[{"key":"2026091109094392000_cit1","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1021\/acsinfecdis.5c00727","article-title":"Antimicrobial Activity,\nPreliminary Safety, and Pharmacokinetics Assessment of 2\u20133:\nA Pleuromutilin-Derived Compound","author":"Zhao","year":"2025","journal-title":"ACS 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Agr. Food Chem."},{"key":"2026091109094392000_cit4","doi-asserted-by":"publisher","first-page":"e00502","DOI":"10.1128\/AAC.00502-17","article-title":"NP108, an Antimicrobial Polymer with\nActivity against\nMethicillin- and Mupirocin-Resistant Staphylococcus Aureus","volume":"61","author":"Mercer","year":"2017","journal-title":"Antimicrob. Agents Ch."},{"key":"2026091109094392000_cit5","doi-asserted-by":"publisher","first-page":"2087","DOI":"10.1080\/14756366.2021.1977931","article-title":"A Click Chemistry Approach to Pleuromutilin Derivatives,\nEvaluation\nof Anti-MRSA Activity and Elucidation of Binding Mode by Surface Plasmon\nResonance and Molecular Docking","volume":"36","author":"Zhang","year":"2021","journal-title":"J. Enzym. Inhib.\nMed. Chem."},{"key":"2026091109094392000_cit6","doi-asserted-by":"publisher","first-page":"53","DOI":"10.2174\/138955712798868968","article-title":"Pleuromutilin and its Derivatives-the Lead Compounds\nfor Novel Antibiotics","volume":"12","author":"Tang","year":"2012","journal-title":"Mini-Rev. Med. Chem."},{"key":"2026091109094392000_cit7","doi-asserted-by":"publisher","first-page":"e02317","DOI":"10.1128\/AAC.02388-17","article-title":"Unraveling the Metabolic Routes of\nRetapamulin: Insights into Drug Development of Pleuromutilins","volume":"62","author":"Sun","year":"2018","journal-title":"Antimicrob. Agents Ch."},{"key":"2026091109094392000_cit8","doi-asserted-by":"publisher","first-page":"9201","DOI":"10.1021\/jf5012402","article-title":"In Vitro and\nin Vivo Metabolite Profiling of Valnemulin Using Ultraperformance\nLiquid Chromatography-Quadrupole\/Time-of-Flight Hybrid Mass Spectrometry","volume":"62","author":"Yang","year":"2014","journal-title":"J. Agr. 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Chem."},{"key":"2026091109094392000_cit12","doi-asserted-by":"publisher","DOI":"10.3390\/molecules25040878","article-title":"Antibacterial Activity\nand Pharmacokinetic Profile\nof a Promising Antibacterial Agent: 22-(2-Amino-Phenylsulfanyl)-22-Deoxypleuromutilin","volume":"25","author":"Zuo","year":"2020","journal-title":"Molecules"},{"key":"2026091109094392000_cit13","doi-asserted-by":"publisher","first-page":"264","DOI":"10.3390\/pathogens9040264","article-title":"Biofilm Production Ability, Virulence\nand Antimicrobial Resistance\nGenes in Staphylococcus Aureus from\nVarious Veterinary Hospitals","volume":"9","author":"Chen","year":"2020","journal-title":"Pathogens"},{"key":"2026091109094392000_cit14","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1016\/j.jgar.2023.08.015","article-title":"The Occurrence and Contamination\nof optra-Positive Methicillin-Resistant Staphylococcus Aureus from Duck Farms in Guangdong, China","volume":"35","author":"Li","year":"2023","journal-title":"J. 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Int."},{"key":"2026091109094392000_cit23","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.03675-23","article-title":"Pharmacokinetic\/Pharmacodynamic\nIntegration of Amphenmulin: A Novel Pleuromutilin Derivative against Mycoplasma Gallisepticum","volume":"12","author":"Wang","year":"2024","journal-title":"Microbiol.\nSpectrum"},{"key":"2026091109094392000_cit24","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2019.111594","article-title":"Design, Synthesis and\nBiological Evaluation of Novel Pleuromutilin\nDerivatives Possessing Acetamine Phenyl Linker","volume":"181","author":"Jin","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"2026091109094392000_cit25","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1038\/s41570-023-00569-9","article-title":"Small Molecule Approaches to Targeting\nRNA","volume":"8","author":"Kovachka","year":"2024","journal-title":"Nat. Rev. Chem."},{"key":"2026091109094392000_cit26","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2024.117061","article-title":"Design, Synthesis,\nand Biological Evaluation of Novel Pleuromutilin Derivatives with\nMethicillin-Resistant Staphylococcus Aureus -Targeting Phenol Linker Groups","volume":"282","author":"Yi","year":"2025","journal-title":"Eur. J. Med.\nChem."},{"key":"2026091109094392000_cit27","unstructured":"Craig, W. A.; Andes, D.; Ivezic-Schoenfeld, Z.; Wicha, W. W.; Novak, R.\n          In Vivo Pharmacodynamic Activity\nof BC-3781. 2010."},{"key":"2026091109094392000_cit28","doi-asserted-by":"publisher","DOI":"10.1002\/bmc.70052","article-title":"In Vitro Plasma Protein\nBinding Determination of Lefamulin by Equilibrium Dialysis and High-Performance\nLiquid Chromatography Coupled with Evaporative Light Scattering Detector","volume":"39","author":"Xin","year":"2025","journal-title":"Biomed. Chromatogr."},{"key":"2026091109094392000_cit29","doi-asserted-by":"publisher","first-page":"1627","DOI":"10.1111\/cbdd.13328","article-title":"Synthesis and Antibacterial Activities\nof Novel Pleuromutilin Derivatives\nBearing an Aminothiophenol Moiety","volume":"92","author":"Zhang","year":"2018","journal-title":"Chem. Biol.\nDrug Des"},{"key":"2026091109094392000_cit30","doi-asserted-by":"publisher","DOI":"10.1128\/jcm.01623-23","article-title":"Overview\nof Changes in the Clinical and Laboratory\nStandards Institute Performance Standards for Antimicrobial Susceptibility\nTesting: M100 32Nd and 33Rd Editions","volume":"63","author":"Schuetz","year":"2025","journal-title":"J. Clin.\nMicrobiol."},{"key":"2026091109094392000_cit31","doi-asserted-by":"publisher","first-page":"5061","DOI":"10.1021\/acs.jmedchem.2c02135","article-title":"Discovery of Quaternized\nPyridine-Thiazole-Pleuromutilin Derivatives with Broad-Spectrum Antibacterial\nand Potent Anti-MRSA Activity","volume":"66","author":"Xia","year":"2023","journal-title":"J. Med. Chem."},{"key":"2026091109094392000_cit32","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-022-04164-4","article-title":"Matching Amino\nAcids Membrane Preference Profile to\nImprove Activity of Antimicrobial Peptides","volume":"5","author":"Kim","year":"2022","journal-title":"Commun. Biol."},{"key":"2026091109094392000_cit33","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2021.113624","article-title":"Design, Synthesis and Biological Evaluation of Pleuromutilin-Schiff\nBase Hybrids as Potent Anti-MRSA Agents in Vitro and in Vivo","volume":"223","author":"Li","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"2026091109094392000_cit34","doi-asserted-by":"publisher","first-page":"3304","DOI":"10.1093\/nar\/gkw161","article-title":"Suppression of Gyrase-Mediated\nResistance\nby C7 Aryl Fluoroquinolones","volume":"44","author":"Malik","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"2026091109094392000_cit35","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1038\/ja.2011.101","article-title":"Post-Antibiotic\nEffect of Colistin, Alone and in Combination\nwith Amikacin, on Pseudomonas Aeruginosa Strains Isolated from Cystic\nFibrosis Patients","volume":"65","author":"Bozkurt-Gu\u0308zel","year":"2012","journal-title":"J. Antibiot."},{"key":"2026091109094392000_cit36","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2023.106353","article-title":"Antibiotic Resistance and Drug Modification:\nSynthesis, Characterization\nand Bioactivity of Newly Modified Potent Pleuromutilin Derivatives\nwith a Substituted Piperazine Moiety","volume":"132","author":"Yi","year":"2023","journal-title":"Bioorg.\nChem."},{"key":"2026091109094392000_cit37","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2023.115882","article-title":"Synthesis\nand Evaluation of Novel\nPleuromutilin Derivatives Targeting the 50S Ribosomal Subunit for\nAntibacterial Ability","volume":"262","author":"Liu","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"2026091109094392000_cit38","doi-asserted-by":"publisher","first-page":"1453","DOI":"10.1080\/17460441.2021.1961741","article-title":"An Update\non the Importance of Plasma Protein Binding in Drug Discovery and\nDevelopment","volume":"16","author":"Di","year":"2021","journal-title":"Expert Opin. Drug Dis."},{"key":"2026091109094392000_cit39","doi-asserted-by":"publisher","first-page":"1019","DOI":"10.2147\/IDR.S399150","article-title":"Pharmacokinetics\nand Pharmacodynamics of a Novel Vancomycin Derivative LYSC98 in a\nMurine Thigh Infection Model against Staphylococcus Aureus","volume":"Volume 16","author":"He","year":"2023","journal-title":"Infect. Drug Resist."}],"container-title":["ACS Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsinfecdis.6c00558","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article-pdf\/12\/9\/3230\/67343011\/acsinfecdis.6c00558.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article-pdf\/12\/9\/3230\/67343011\/acsinfecdis.6c00558.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T13:36:45Z","timestamp":1789133805000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article\/12\/9\/3230\/5323187\/In-Vitro-and-In-Vivo-Activity-against"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,24]]},"references-count":39,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,8,24]]},"published-print":{"date-parts":[[2026,9,11]]}},"URL":"https:\/\/doi.org\/10.1021\/acsinfecdis.6c00558","relation":{},"ISSN":["2373-8227"],"issn-type":[{"value":"2373-8227","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,24]]}}}