{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T21:21:21Z","timestamp":1781731281590,"version":"3.54.5"},"reference-count":65,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T00:00:00Z","timestamp":1760400000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100001774","name":"New Jersey Health Foundation","doi-asserted-by":"publisher","award":["PC154-23"],"award-info":[{"award-number":["PC154-23"]}],"id":[{"id":"10.13039\/100001774","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011132","name":"Rutgers, The State University of New Jersey","doi-asserted-by":"publisher","award":["Busch Biomedical Grant Program"],"award-info":[{"award-number":["Busch Biomedical Grant Program"]}],"id":[{"id":"10.13039\/100011132","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000266","name":"Engineering and Physical Sciences Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000266","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Multidrug resistance in the Gram-negative bacterial pathogen <jats:italic>Acinetobacter baumannii<\/jats:italic> is a global public health threat, highlighting a critical need for drug development. FtsZ is an essential cell division protein that is an appealing target for new antibacterial agents. Benzamide-based FtsZ inhibitors have been developed that exhibit potent activity against Gram-positive pathogens, but poor activity against <jats:italic>A. baumannii<\/jats:italic> and other clinically significant Gram-negative pathogens. In this connection, we have initiated a program to enhance activity of benzamide FtsZ inhibitors via conjugation to iron-coordinating siderophore moieties that promote cellular uptake through endogenous bacterial siderophore-iron uptake pathways. Here, we describe a second-generation FtsZ inhibitor-siderophore conjugate (RUP7), in which an oxazole-benzamide FtsZ inhibitor is conjugated to acinetobactin, a principal native siderophore of <jats:italic>A. baumannii<\/jats:italic>. In iron-limiting conditions that are typically present at common sites of <jats:italic>A. baumannii<\/jats:italic> infection, RUP7 exhibits significantly enhanced activity against a library of <jats:italic>A. baumannii<\/jats:italic> clinical isolates relative to the non-conjugated FtsZ inhibitor (RUP2) or a first-generation conjugate (RUP4) in which RUP2 has been conjugated to a chlorocatechol siderophore functionality. This enhanced activity is correlated with markedly improved cellular uptake, perhaps via the BauABCDEF acinetobactin-iron uptake system, the expression of which is highly upregulated in iron-limiting conditions. RUP7 exhibits significant bactericidal synergy against <jats:italic>A. baumannii<\/jats:italic> when combined with clinical antibiotics that target penicillin binding protein 3 (PBP3 or FtsI), including aztreonam, piperacillin:tazobactam, cefsulodin, and ceftazidime. In the aggregate, our results highlight the combination of design-optimized FtsZ inhibitor-siderophore conjugates and PBP3-targeting antibiotics as an appealing therapeutic strategy for the treatment of <jats:italic>A. baumannii<\/jats:italic> infections.<\/jats:p>","DOI":"10.1371\/journal.pone.0334409","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T17:29:20Z","timestamp":1760462960000},"page":"e0334409","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["A FtsZ inhibitor-acinetobactin conjugate with enhanced cellular uptake in Acinetobacter baumannii acts synergistically in combination with PBP3-targeting antibiotics"],"prefix":"10.1371","volume":"20","author":[{"given":"Eric J.","family":"Bryan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoltan","family":"Szekely","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huizhou","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4097-4331","authenticated-orcid":true,"given":"Lucile","family":"Moyni\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacques Y.","family":"Roberge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0113-0849","authenticated-orcid":true,"given":"Daniel 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