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While the main advantage explaining their enhanced antibiotic activity is believed to be improved membrane permeability, other factors remain underexplored. This study evaluates three siderophore-\u03b2-lactam compounds: a bis-catechol siderophore linked to ampicillin or loracarbef, and a mixed bis-catechol-mono-hydroxamate siderophore linked to cefaclor. Minimal inhibitory concentrations showed that siderophore conjugation could enhance \u03b2-lactam efficacy by over 8000-fold. Comparison with unconjugated \u03b2-lactams revealed a complex interplay between \u03b2-lactamase susceptibility, competition with endogenous siderophore, membrane uptake, and binding to penicillin-binding proteins (PBPs). Enhanced PBP binding, particularly in\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    , emerged as a key factor contributing to improved bacterial inhibition by siderophore-\u03b2-lactam conjugates. Overall, the study provides insights into how siderophore conjugation enhances \u03b2-lactam activity and the therapeutic potential of the conjugates as narrow or broad-spectrum antibiotics.\n                  <\/jats:p>","DOI":"10.1038\/s42003-025-08898-9","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T12:25:39Z","timestamp":1762431939000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Unraveling the mechanisms behind the enhanced efficacy of \u03b2-lactam-based sideromycins"],"prefix":"10.1038","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-7217-3768","authenticated-orcid":false,"given":"Evelyne","family":"Lacasse","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renaud","family":"Binette","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9lo\u00efse","family":"Guibout","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-Ming","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuka","family":"Ghosh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2032-7970","authenticated-orcid":false,"given":"Pierre-Luc","family":"Boudreault","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3704-8214","authenticated-orcid":false,"given":"Marvin J.","family":"Miller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5031-345X","authenticated-orcid":false,"given":"Fran\u00e7ois","family":"Malouin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,6]]},"reference":[{"key":"8898_CR1","doi-asserted-by":"crossref","unstructured":"Neu, H. 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