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During screening efforts to discover new broad-spectrum antibiotic compounds from marine sponge samples, we identified a new analog of the peptidyl nucleoside antibiotic blasticidin S that exhibited up to 16-fold-improved potency against a range of laboratory and clinical bacterial strains which we named P10. Whole-genome sequencing of laboratory-evolved strains of\n            <jats:named-content content-type=\"genus-species\">Staphylococcus aureus<\/jats:named-content>\n            resistant to blasticidin S and P10, combined with genome-wide assessment of the fitness of barcoded\n            <jats:named-content content-type=\"genus-species\">Escherichia coli<\/jats:named-content>\n            knockout strains in the presence of the antibiotics, revealed that restriction of cellular access was a key feature in the development of resistance to this class of drug. In particular, the gene encoding the well-characterized multidrug efflux pump NorA was found to be mutated in 69% of all\n            <jats:named-content content-type=\"genus-species\">S. aureus<\/jats:named-content>\n            isolates resistant to blasticidin S or P10. Unexpectedly, resistance was associated with inactivation of\n            <jats:italic>norA<\/jats:italic>\n            , suggesting that the NorA transporter facilitates cellular entry of peptidyl nucleosides in addition to its known role in the efflux of diverse compounds, including fluoroquinolone antibiotics.\n          <\/jats:p>","DOI":"10.1128\/aac.02635-16","type":"journal-article","created":{"date-parts":[[2017,4,4]],"date-time":"2017-04-04T00:37:41Z","timestamp":1491266261000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":14,"title":["A New Natural Product Analog of Blasticidin S Reveals Cellular Uptake Facilitated by the NorA Multidrug Transporter"],"prefix":"10.1128","volume":"61","author":[{"given":"Jack R.","family":"Davison","sequence":"first","affiliation":[{"name":"Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeff","family":"Piotrowski","sequence":"additional","affiliation":[{"name":"Great Lakes Bioenergy Research Center, University of Wisconsin\u2014Madison, Madison, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harold E.","family":"Smith","sequence":"additional","affiliation":[{"name":"Genomics Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2203-0852","authenticated-orcid":false,"given":"Carole A.","family":"Bewley","sequence":"additional","affiliation":[{"name":"Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, 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