Metabolic Adaptation in Methicillin-Resistant Pneumonia.

TitleMetabolic Adaptation in Methicillin-Resistant Pneumonia.
Publication TypeJournal Article
Year of Publication2019
AuthorsGabryszewski SJ, Lung TWong Fok, Annavajhala MK, Tomlinson KL, Riquelme SA, Khan IN, Noguera LP, Wickersham M, Zhao A, Mulenos AM, Peaper D, Koff JL, Uhlemann A-C, Prince A
JournalAm J Respir Cell Mol Biol
Volume61
Issue2
Pagination185-197
Date Published2019 Aug
ISSN1535-4989
Abstract

Methicillin-resistant (MRSA) is a versatile human pathogen that is 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. 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 , which catalyzes the interconversion of fumarate and malate. Elevated fumarate levels promoted 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.

DOI10.1165/rcmb.2018-0389OC
Alternate JournalAm. J. Respir. Cell Mol. Biol.
PubMed ID30742488
PubMed Central IDPMC6670030
Grant ListR35 HL135800 / HL / NHLBI NIH HHS / United States