{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:19:14Z","timestamp":1792790354909,"version":"4.5.0"},"posted":{"date-parts":[[2026,3,22]]},"group-title":"Pharmacology and Toxicology","reference-count":54,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,22]],"date-time":"2026-03-22T00:00:00Z","timestamp":1774137600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"NIAID","award":["R01AI179080-01"],"award-info":[{"award-number":["R01AI179080-01"]}],"id":[{"id":"https:\/\/ror.org\/043z4tv69","id-type":"ROR","asserted-by":"crossref"}]},{"name":"NIAID","award":["1R01AI178975-01"],"award-info":[{"award-number":["1R01AI178975-01"]}],"id":[{"id":"https:\/\/ror.org\/043z4tv69","id-type":"ROR","asserted-by":"crossref"}]},{"name":"NIGMS","award":["R35GM124893"],"award-info":[{"award-number":["R35GM124893"]}],"id":[{"id":"https:\/\/ror.org\/04q48ey07","id-type":"ROR","asserted-by":"crossref"}]},{"award":["INV-080847"],"award-info":[{"award-number":["INV-080847"]}],"id":[{"id":"https:\/\/ror.org\/0456r8d26","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  The emergence of drug-resistant strains of\n                  <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                  makes anti-tubercular drug development a critical priority. Griselimycin is a cyclic peptide that targets the essential DNA sliding clamp of\n                  <jats:italic>M. tuberculosis<\/jats:italic>\n                  . While griselimycin is a promising antimycobacterial compound, its poorly understood structure-activity relationship has stalled derivatization. To investigate the contribution of each amino acid towards its activity, we assessed the antibiotic activity of an alanine scan library in\n                  <jats:italic>M. tuberculosis<\/jats:italic>\n                  . Incorporation of an\n                  <jats:italic>N<\/jats:italic>\n                  -terminal fluorophore enabled visualization of griselimycin accumulation inside of mycobacteria-infected macrophage cells. Derivatives containing altered cyclization chemistries, unnatural amino acids, expanded proline side chains, and alkyne handles were assessed, with a final design combining the most potent edits showing increased antibiotic activity. These findings present the comprehensive structure-activity investigation of griselimycin and can be used to rationally design future analogues.\n                <\/jats:p>\n                <jats:sec id=\"s1\">\n                  <jats:title>TABLE OF CONTENTS GRAPHIC<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"712639v2_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.64898\/2026.03.19.712639","type":"posted-content","created":{"date-parts":[[2026,3,22]],"date-time":"2026-03-22T23:30:13Z","timestamp":1774222213000},"source":"Crossref","is-referenced-by-count":2,"title":["Molecular Determinants Governing the Antitubercular Activity of Griselimycin"],"prefix":"10.64898","author":[{"given":"Andrew","family":"Spira","sequence":"first","affiliation":[{"name":"Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sydney M.","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachita","family":"Dash","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah E.","family":"Newkirk","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Lepori","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University of Massachusetts, Amherst, Massachusetts 01003-9298, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanhang Caroline","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University of Massachusetts, Amherst, Massachusetts 01003-9298, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vaskar","family":"Chowdhury","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sobika","family":"Bhandari","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zichen","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean","family":"Chmielewski","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Sloan Siegrist","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University of Massachusetts, Amherst, Massachusetts 01003-9298, United States"},{"name":"Molecular and Cellular Biology Graduate Program, University of Massachusetts, Amherst, Massachusetts 01003-9298, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5676-0725","authenticated-orcid":false,"given":"Marcos M.","family":"Pires","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, United States"},{"name":"Department of Microbiology, Immunology, and Cancer, University of Virginia, Charlottesville, Virginia 22904, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026091812500818000_2026.03.19.712639v2.1","unstructured":"Global Tuberculosis Report 2025. https:\/\/www.who.int\/teams\/global-programme-on-tuberculosis-and-lung-health\/tb-reports\/global-tuberculosis-report-2025 (accessed 2025-12-04)"},{"key":"2026091812500818000_2026.03.19.712639v2.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-024-01025-1"},{"key":"2026091812500818000_2026.03.19.712639v2.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-024-00897-5"},{"key":"2026091812500818000_2026.03.19.712639v2.4","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(25)00118-5"},{"key":"2026091812500818000_2026.03.19.712639v2.5","first-page":"2349","article-title":"[Structure of griselimycin, polypeptide antibiotic extracted Streptomyces cultures","volume":"6","year":"1971","journal-title":"I. 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