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We investigated how MRSA adapts to the human airway to establish chronic infection, as occurs during cystic fibrosis (CF). MRSA isolates from patients with CF that were collected over a 4-year period were analyzed by whole-genome sequencing, transcriptional analysis, and metabolic studies. Persistent MRSA infection was associated with staphylococcal metabolic adaptation, but not changes in immunogenicity. Adaptation was characterized by selective use of the tricarboxylic acid cycle cycle and generation of biofilm, a means of limiting oxidant stress. Increased transcription of specific metabolic genes was conserved in all host-adapted strains, most notably a 10,000-fold increase in fumC, which catalyzes the interconversion of fumarate and malate. Elevated fumarate levels promoted in vitro biofilm production in clinical isolates. Host-adapted strains preferred to assimilate glucose polymers and pyruvate, which can be metabolized to generate N-acetylglucosamine polymers that comprise biofilm. MRSA undergoes substantial metabolic adaptation to the human airway to cause chronic pulmonary infection, and selected metabolites may be useful therapeutically to inhibit infection.<\/jats:p>","DOI":"10.1165\/rcmb.2018-0389oc","type":"journal-article","created":{"date-parts":[[2019,2,11]],"date-time":"2019-02-11T14:54:06Z","timestamp":1549896846000},"page":"185-197","source":"Crossref","is-referenced-by-count":59,"title":["Metabolic Adaptation in Methicillin-Resistant\n                    <i>Staphylococcus aureus<\/i>\n                    Pneumonia"],"prefix":"10.1093","volume":"61","author":[{"given":"Stanislaw J.","family":"Gabryszewski","sequence":"first","affiliation":[{"name":"Department of Pediatrics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tania","family":"Wong Fok Lung","sequence":"additional","affiliation":[{"name":"Department of Pediatrics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Medini K.","family":"Annavajhala","sequence":"additional","affiliation":[{"name":"Department of Medicine, and"},{"name":"Microbiome and Pathogen Genomics Core, Department of Medicine, Columbia University Irving Medical Center, New York, New York; 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