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Adv."],"published-print":{"date-parts":[[2026,5,8]]},"abstract":"<jats:p>\n                    A comprehensive genetic landscape of antibiotic sensitivity in\n                    <jats:italic toggle=\"yes\">Staphylococcus aureus<\/jats:italic>\n                    is lacking. Using genome-scale CRISPR-interference libraries, we systematically quantified global gene fitness across 10 antibiotics and uncovered hundreds of significant antibiotic-gene interactions. Essential genes dominated these interactions, a finding not revealed by transposon-based studies. CRISPR interference repression of transcriptional and translational processes desensitized bacteria to multiple antibiotics. In contrast, repression of cell wall synthesis\/cell division (CC), DNA replication\/DNA recombination (DD), coenzyme A biosynthesis, and riboflavin metabolism strongly sensitized bacteria to antibiotics. Network and genetic analyses further revealed synergistic genetic interactions (GIs) within these bioprocesses, including an extensive CC-DD subnetwork. Only a subset of CC-DD synergies was dependent on the cell division inhibitor SosA. Informed by these GIs, we identified multiple drug-drug combinations with potent synergistic activity against multidrug-resistant\n                    <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                    . Our detailed profiling of drug-gene, gene-gene, and drug-drug interactions reveals important functional relationships among essential genes and defines a vulnerability landscape to guide drug target discovery and effective combination therapies.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aeb9875","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T09:53:19Z","timestamp":1778579599000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":2,"title":["The genetic landscape of antibiotic sensitivity in\n                    <i>Staphylococcus aureus<\/i>"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-1858-9522","authenticated-orcid":true,"given":"Wan","family":"Li","sequence":"first","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9390-8194","authenticated-orcid":true,"given":"Menghan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Columbia University, New York, NY 10027, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7387-0312","authenticated-orcid":true,"given":"Panos","family":"Oikonomou","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Columbia University, New York, NY 10027, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sydney","family":"Blattman","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Columbia University, New York, NY 10027, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7347-9823","authenticated-orcid":true,"given":"Mirela","family":"Berisa","sequence":"additional","affiliation":[{"name":"Metabolomics Core, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0721-9879","authenticated-orcid":true,"given":"Falguni","family":"Paul","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Hettleman","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0777-1437","authenticated-orcid":true,"given":"Joseph","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3130-0121","authenticated-orcid":true,"given":"Qiaoyu","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3579-4268","authenticated-orcid":true,"given":"Howe","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2183-4162","authenticated-orcid":true,"given":"Saeed","family":"Tavazoie","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Columbia University, New York, NY 10027, USA."},{"name":"Department of Systems Biology, Columbia University, New York, NY 10032, USA."},{"name":"Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1744-3129","authenticated-orcid":true,"given":"Wenyan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA."},{"name":"Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(24)01867-1"},{"key":"e_1_3_2_3_2","unstructured":"J. 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