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Updated: May 10, 2026

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Published on: February 14, 2025
The genetic landscape of antibiotic sensitivity in Staphylococcus aureus
Wan Li1, Menghan Liu2, Panos Oikonomou2
1Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Abstract:
A comprehensive genetic landscape of antibiotic sensitivity in Staphylococcus aureus 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 S. aureus. 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.
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