{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T19:39:19Z","timestamp":1793129959044,"version":"4.5.0"},"reference-count":54,"publisher":"American Society for Microbiology","issue":"10","license":[{"start":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T00:00:00Z","timestamp":1791936000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T00:00:00Z","timestamp":1791936000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["2547373"],"award-info":[{"award-number":["2547373"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007155","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/X502923\/1"],"award-info":[{"award-number":["MR\/X502923\/1"]}],"id":[{"id":"10.13039\/501100007155","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Schlumberger Faculty for the Future"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2026,10,14]]},"abstract":"ABSTRACT<\/jats:title>\n \n \n \n Antimicrobial peptides (AMPs) display rapid bactericidal activity\n in vitro<\/jats:italic>\n , but have largely failed as systemically administered therapeutics, indicating that intrinsic potency alone does not predict\n in vivo<\/jats:italic>\n efficacy. Here, we examine how pharmacokinetics, stereochemistry, and host context shape early\n in vivo<\/jats:italic>\n activity using pleurocidin-derived peptides. The\n D<\/jats:sc>\n -amino-acid analog D-P-KR rapidly eradicates priority bacterial pathogens within minutes\n in vitro<\/jats:italic>\n , achieving this at low multiples of the minimum inhibitory concentration (MIC) for\n Staphylococcus aureus<\/jats:italic>\n but requiring higher multiples for Gram-negative species. Near-infrared imaging of fluorescently labeled enantiomers reveals that stereochemistry strongly influences systemic behavior, with D-enantiomers showing reduced renal and hepatobiliary clearance and increased exposure following intravenous administration. Despite these favorable properties, systemic D-P-KR does not reduce pulmonary bacterial burden within 2 h of treatment in mouse models of\n S. aureus<\/jats:italic>\n or\n Klebsiella pneumoniae<\/jats:italic>\n pneumonia. In contrast, increasing exposure through short intravenous infusion produces a rapid, exposure-dependent reduction in pulmonary neutrophil recruitment in\n S. aureus<\/jats:italic>\n infection, without corresponding early changes in bacterial burden. This effect is not observed in the disseminating\n K. pneumoniae<\/jats:italic>\n model. These findings demonstrate a dissociation between rapid\n in vitro<\/jats:italic>\n killing, early bacterial clearance, and host-response modulation, and show that early\n in vivo<\/jats:italic>\n AMP activity is governed primarily by systemic exposure and infection context. More broadly, this work highlights the need to integrate pharmacokinetics, dosing strategy, and host response when evaluating antimicrobial peptides for systemic use.\n <\/jats:p>\n \n IMPORTANCE<\/jats:title>\n \n Antimicrobial peptides can kill bacteria far more rapidly than most conventional antibiotics, yet very few have succeeded as systemically administered drugs. This study shows that differences in peptide stereochemistry profoundly influence how antimicrobial peptides distribute within the body and how long effective exposure can be maintained. Our findings demonstrate that strong antibacterial activity\n in vitro<\/jats:italic>\n does not necessarily translate into early bacterial clearance\n in vivo<\/jats:italic>\n , but that delivery strategies can still affect host responses during infection. By linking peptide stereochemistry, systemic exposure, and biological outcomes, this work highlights why many antimicrobial peptides struggle to translate clinically and underscores the need to prioritize pharmacokinetics, formulation, and dosing strategy alongside antibacterial potency during antimicrobial peptide development.\n <\/jats:p>\n <\/jats:sec>\n <\/jats:sec>","DOI":"10.1128\/mbio.01718-26","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T13:00:17Z","timestamp":1787922017000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Enantiomer-dependent biodistribution and exposure determine the\n in vivo<\/i>\n behavior of a pleurocidin-derived antimicrobial peptide"],"prefix":"10.1128","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-8738-4137","authenticated-orcid":true,"given":"Janis","family":"Romanopulos","sequence":"first","affiliation":[{"name":"Institute of Pharmaceutical Science, School of Cancer & Pharmaceutical Sciences, King\u2019s College London","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Cressey","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Science, School of Cancer & Pharmaceutical Sciences, King\u2019s College London","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte K.","family":"Hind","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/018h10037","id-type":"ROR","asserted-by":"publisher"}],"name":"Antimicrobial Discovery, Development and Diagnostics (AD3), Countermeasures Development, Evaluation and Preparedness, UK Health Security Agency","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seong-Heun","family":"Kim","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Science, School of Cancer & Pharmaceutical Sciences, King\u2019s College London","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zayed A.","family":"Shalim","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Science, School of Cancer & Pharmaceutical Sciences, King\u2019s College London","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadiya","family":"Mohamed Akram","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Science, School of Cancer & Pharmaceutical Sciences, King\u2019s College London","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hala","family":"Alnasif Alhadi","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Science, School of Cancer & Pharmaceutical Sciences, King\u2019s College London","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amelia","family":"Claxton","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Science, School of Cancer & Pharmaceutical Sciences, King\u2019s College London","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuang","family":"You","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Science, School of Cancer & Pharmaceutical Sciences, King\u2019s College London","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna V.","family":"Kelis","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Science, School of Cancer & Pharmaceutical Sciences, King\u2019s College London","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bailey","family":"Ramsden","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Science, School of Cancer & Pharmaceutical Sciences, King\u2019s College London","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siham","family":"Memdouh","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Science, School of Cancer & Pharmaceutical Sciences, King\u2019s College London","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana C.","family":"Jacob","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Science, School of Cancer & Pharmaceutical Sciences, King\u2019s College London","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tam T.","family":"Bui","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0220mzb33","id-type":"ROR","asserted-by":"publisher"}],"name":"Centre for Biomolecular Spectroscopy and Randall Division of Cell and Molecular Biophysics, King's College London Randall Centre for Cell & Molecular Biophysics","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon J.","family":"Cleary","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Science, School of Cancer & Pharmaceutical Sciences, King\u2019s College London","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maya","family":"Thanou","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Science, School of Cancer & Pharmaceutical Sciences, King\u2019s College London","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard 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