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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,1,7]]},"abstract":"<jats:p>\n                    Infections caused by gram-negative pathogens continue to be a major risk to human health because of the innate antibiotic resistance endowed by their unique cell membrane architecture. Nature has developed an elegant solution to target gram-negative strains, namely by conjugating toxic antibiotic warheads to a suitable carrier to facilitate the active import of the drug to a specific target organism. Microcin C7 (McC) is a Trojan horse peptide\u2013conjugated antibiotic that specifically targets enterobacteria by exploiting active import through oligopeptide transport systems. Here, we characterize the molecular mechanism of McC recognition by YejA, the solute binding protein of the\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    oligopeptide transporter. Structure-guided mutational and functional analysis elucidates the determinants of substrate recognition. We demonstrate that the peptide carrier can serve as a passport for the entry of molecules that are otherwise not taken into\n                    <jats:italic>E. coli<\/jats:italic>\n                    cells. We show that peptide conjugation can remodel the antibiotic spectrum of clinically relevant parent compounds. Bioinformatics analysis reveals a broad distribution of YejA-like transporters in only the Proteobacteria, underscoring the potential for the development of Trojan horse antibiotics that are actively imported into such gram-negative bacteria.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2319483121","type":"journal-article","created":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T13:42:02Z","timestamp":1735652522000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":16,"title":["Trojan horse peptide conjugates remodel the activity spectrum of clinical antibiotics"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2162-2477","authenticated-orcid":false,"given":"Shangwen","family":"Luo","sequence":"first","affiliation":[{"name":"State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University","place":["Lanzhou, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Rong","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University","place":["Lanzhou, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2718-4366","authenticated-orcid":false,"given":"Xiao-Tong","family":"Gong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University","place":["Lanzhou, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5043-9810","authenticated-orcid":false,"given":"Alexey","family":"Kulikovsky","sequence":"additional","affiliation":[{"name":"Institute of Gene Biology, Russian Academy of Sciences","place":["Moscow, Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7168-9018","authenticated-orcid":false,"given":"Feng","family":"Qu","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Imperial College London","place":["London, United Kingdom"]},{"name":"Rutherford Appleton Laboratory, Research Complex at Harwell","place":["Didcot, Oxfordshire, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5727-4721","authenticated-orcid":false,"given":"Konstantinos","family":"Beis","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Imperial College London","place":["London, United Kingdom"]},{"name":"Rutherford Appleton Laboratory, Research Complex at Harwell","place":["Didcot, Oxfordshire, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9706-450X","authenticated-orcid":false,"given":"Konstantin","family":"Severinov","sequence":"additional","affiliation":[{"name":"Institute of Gene Biology, Russian Academy of Sciences","place":["Moscow, Russia"]},{"name":"Waksman Institute for Microbiology, Rutgers University","place":["Piscataway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9225-5534","authenticated-orcid":false,"given":"Svetlana","family":"Dubiley","sequence":"additional","affiliation":[{"name":"Institute of Gene Biology, Russian Academy of Sciences","place":["Moscow, Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3142-5629","authenticated-orcid":false,"given":"Xinxin","family":"Feng","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology and Nanomedicine, State Key Laboratory of Chemo\/Biosensing and Chemometrics, Hunan University","place":["Hunan, People\u2019s Republic of China"]},{"name":"School of Chemistry and Chemical Engineering, Hunan University","place":["Hunan, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1743-2163","authenticated-orcid":false,"given":"Shi-Hui","family":"Dong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University","place":["Lanzhou, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1790-1334","authenticated-orcid":false,"given":"Satish K.","family":"Nair","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Illinois","place":["Urbana"]},{"name":"Carl R. Woese Institute for Genomic Biology, University of Illinois","place":["Urbana"]},{"name":"Center for Biophysics and Quantitative Biology, University of Illinois","place":["Urbana"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,12,31]]},"reference":[{"key":"e_1_3_4_1_2","volume-title":"Global Priority List of Antibiotic-Resistant Bacteria to Guide Research, Discovery, and Development of New Antibiotics","author":"Tacconelli E.","year":"2017","unstructured":"E. Tacconelli, N. 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K. Nair S.-H. Dong Complex structure of YejA with Microcin C7. Protein Data Bank. https:\/\/www.rcsb.org\/structure\/8FSQ. Deposited 11 January 2023.","DOI":"10.2210\/pdb8fsq\/pdb"},{"key":"e_1_3_4_60_2","doi-asserted-by":"crossref","unstructured":"S. K. Nair S.-H. Dong Complex structure of YejA with fMccA. Protein Data Bank. https:\/\/www.rcsb.org\/structure\/8FSR. Deposited 11 January 2023.","DOI":"10.2210\/pdb8fsr\/pdb"},{"key":"e_1_3_4_61_2","doi-asserted-by":"crossref","unstructured":"S. K. Nair S.-H. Dong Complex structure of YejA-S481A with Microcin C7. Protein Data Bank. https:\/\/www.rcsb.org\/structure\/8FSS. Deposited 11 January 2023.","DOI":"10.2210\/pdb8fss\/pdb"},{"key":"e_1_3_4_62_2","doi-asserted-by":"crossref","unstructured":"K. Beis F. Qu Crystal structure of the substrate-binding protein YejA in complex with peptide fragment. Protein Data Bank. https:\/\/www.rcsb.org\/structure\/7Z6F. 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