Rationale
Methicillin-resistant Staphylococcus aureus (MRSA) is a versatile human pathogen associated with diverse types of infections, ranging from benign colonization to sepsis. We postulated that MRSA must undergo specific genotypic and phenotypic changes to cause chronic pulmonary disease.
Objectives
We investigated how MRSA adapts to the human airway to establish chronic infection, as occurs during cystic fibrosis (CF).
Methods
MRSA isolates from patients with cystic fibrosis collected over a four-year period were analyzed by whole-genome sequencing, transcriptional analysis, and metabolic studies.
Measurements and Main Results
Persistent MRSA infection was associated with staphylococcal metabolic adaptation, not changes in immunogenicity. Adaptation was characterized by selective use of the TCA cycle and generation of biofilm, a means of limiting oxidant stress. Increased transcription of specific metabolic genes was conserved in all hostadapted strains, most notably a 10,000-fold increase in fumC that 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.
Conclusions
MRSA undergoes substantial metabolic adaptation to the human airway to cause chronic pulmonary infection, and selected metabolites may be useful therapeutically to inhibit infection.