{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T13:52:35Z","timestamp":1791381155052,"version":"4.3.3"},"reference-count":24,"publisher":"American Society for Microbiology","issue":"10","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2026,10,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Odilorhabdins (ODLs) are a novel class of peptide antibiotics that inhibit bacterial translation by binding to the 30S ribosomal subunit.\n                      <jats:italic toggle=\"yes\">Xenorhabdus nematophila<\/jats:italic>\n                      , an ODL-producing bacterium, encodes a highly specialized self-resistance acetyltransferase, OatA, that inactivates ODLs via primary amine modification. In this study, we investigated the structural determinants governing susceptibility of the natural compound NOSO-95C to OatA-mediated inactivation. Using an alanine-scanning library, we identified\n                      <jats:italic toggle=\"yes\">N<\/jats:italic>\n                      -terminal lysine (Lys\n                      <jats:sub>1<\/jats:sub>\n                      ) as the key structural determinant of acetyltransferase susceptibility. Expression of\n                      <jats:italic toggle=\"yes\">oatA<\/jats:italic>\n                      in\n                      <jats:italic toggle=\"yes\">E. coli<\/jats:italic>\n                      increased the MIC of NOSO-95C by 64-fold due to rapid OatA-mediated acetylation. In contrast, analog\n                      <jats:bold>1<\/jats:bold>\n                      (Lys1\u2192Ala) was no longer discriminated between Oat-A expressing and non-expressing strains, and remained 95.4% unacetylated after 4 h of incubation. Functional assays confirmed that analog\n                      <jats:bold>1<\/jats:bold>\n                      retains potent translation inhibition and antibacterial activity despite enzyme exposure. Furthermore, OatA failed to inactivate other amine-containing clinical antibiotics such as aminoglycosides, penicillin, or polymyxins. These results indicate that the side chain of\n                      <jats:italic toggle=\"yes\">N<\/jats:italic>\n                      -terminal lysine is essential for efficient OatA-mediated acetylation of ODLs. Moreover, this single residue can be modified to enable ODLs to evade enzymatic inactivation while preserving their primary mechanism of action. This work provides a clear structure-activity framework for the rational design of next-generation ODLs with enhanced stability against OatA-mediated enzymatic modification.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.00743-26","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T14:53:25Z","timestamp":1789570405000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["N-terminal lysine as a critical determinant of odilorhabdin susceptibility to inactivation by the self-resistance acetyltransferase OatA"],"prefix":"10.1128","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4265-9669","authenticated-orcid":true,"given":"Emilie","family":"Racine","sequence":"first","affiliation":[{"name":"Nosopharm","place":["N\u00eemes, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4075-7058","authenticated-orcid":true,"given":"Anne","family":"Lanois-Nouri","sequence":"additional","affiliation":[{"name":"DGIMI, Univ Montpellier, INRAE","place":["Montpellier, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Houard","sequence":"additional","affiliation":[{"name":"Nosopharm","place":["N\u00eemes, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucile","family":"Pantel","sequence":"additional","affiliation":[{"name":"Nosopharm","place":["N\u00eemes, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3901-5133","authenticated-orcid":true,"given":"Alain","family":"Givaudan","sequence":"additional","affiliation":[{"name":"DGIMI, Univ Montpellier, INRAE","place":["Montpellier, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6590-2468","authenticated-orcid":true,"given":"Maxime","family":"Gualtieri","sequence":"additional","affiliation":[{"name":"Nosopharm","place":["N\u00eemes, France"]},{"id":[{"id":"https:\/\/ror.org\/05jhv1f87","id-type":"ROR","asserted-by":"publisher"}],"name":"UPR CHROME, N\u00eemes University","place":["N\u00eemes, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1266"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12915-017-0423-1"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/20.6.783"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.3390\/molecules24193430"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2013.06.010"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22757-1"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mib.2007.05.006"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2018.03177"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-017-0039-9"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2019.02893"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2018.03.001"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.8b00790"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2020.115469"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01016-18"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00139-21"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/aac.00776-22"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.02826-21"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202406389"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00312-11"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/embor.2008.9"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1347"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1021\/acsinfecdis.5c00885"},{"key":"e_1_3_2_24_2","volume-title":"CLSI Document M07-A10","author":"Clinical and Laboratory Standards Institute","year":"2015","unstructured":"Clinical and Laboratory Standards Institute. 2015. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. In CLSI Document M07-A10, 10th ed. 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