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Only a few Fdx derivatives have been synthesized and examined for their biological activity in the 50\u2005years since its discovery. Fdx has a well\u2010studied mechanism of action, namely inhibition of the bacterial RNA polymerase. Yet, the targeted organisms harbor different target protein sequences, which poses a challenge for the rational development of new semisynthetic Fdx derivatives. We introduced substituents on the two phenolic hydroxy groups of Fdx and evaluated the resulting trends in antibiotic activity against\n                    <jats:italic>M.\u2005tuberculosis<\/jats:italic>\n                    ,\n                    <jats:italic>C.\u2005difficile<\/jats:italic>\n                    , and the Gram\u2010negative model organism\n                    <jats:italic>Caulobacter crescentus<\/jats:italic>\n                    . As suggested by the target protein structures, we identified the preferable derivatisation site for each organism. The derivative\n                    <jats:italic>ortho<\/jats:italic>\n                    \u2010methyl Fdx also exhibited activity against the Gram\u2010negative\n                    <jats:italic>C.\u2005crescentus<\/jats:italic>\n                    wild type, a first for fidaxomicin antibiotics. These insights will guide the synthesis of next\u2010generation fidaxomicin antibiotics.\n                  <\/jats:p>","DOI":"10.1002\/cbic.202300570","type":"journal-article","created":{"date-parts":[[2023,9,20]],"date-time":"2023-09-20T06:28:36Z","timestamp":1695191316000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Phenolic Substitution in Fidaxomicin: A Semisynthetic Approach to Antibiotic Activity Across Species**"],"prefix":"10.1002","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6423-7619","authenticated-orcid":false,"given":"Erik","family":"Jung","sequence":"first","affiliation":[{"name":"Department of Chemistry University of Zurich  8057 Z\u00fcrich 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