Details

Autor(en) / Beteiligte

• Frawley, Elaine R
• Karlinsey, Joyce E
• Singhal, Anshika
• Libby, Stephen J
• Doulias, Paschalis-Thomas
• Ischiropoulos, Harry
• Fang, Ferric C
• Storz, Gisela

Titel

Nitric Oxide Disrupts Zinc Homeostasis in Salmonella enterica Serovar Typhimurium

Ist Teil von

• mBio, 2018-08, Vol.9 (4)

Ort / Verlag

United States: American Society for Microbiology

Erscheinungsjahr

2018

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• Nitric oxide (NO·) produced by mammalian cells exerts antimicrobial actions that result primarily from the modification of protein thiols ( -nitrosylation) and metal centers. A comprehensive approach was used to identify novel targets of NO· in serovar Typhimurium (  Typhimurium). Newly identified targets include zinc metalloproteins required for DNA replication and repair (DnaG, PriA, and TopA), protein synthesis (AlaS and RpmE), and various metabolic activities (ClpX, GloB, MetE, PepA, and QueC). The cytotoxic actions of free zinc are mitigated by the ZntA and ZitB zinc efflux transporters, which are required for  Typhimurium resistance to zinc overload and nitrosative stress Zinc efflux also ameliorates NO·-dependent zinc mobilization following internalization by activated macrophages and is required for virulence in NO·-producing mice, demonstrating that host-derived NO· causes zinc stress in intracellular bacteria. Nitric oxide (NO·) is produced by macrophages in response to inflammatory stimuli and restricts the growth of intracellular bacteria. Mechanisms of NO·-dependent antimicrobial actions are incompletely understood. Here, we show that zinc metalloproteins are important targets of NO· in , including the DNA replication proteins DnaG and PriA, which were hypothesized to be NO· targets in earlier studies. Like iron, zinc is a cofactor for several essential proteins but is toxic at elevated concentrations. This study demonstrates that NO· mobilizes free zinc in and that specific efflux transporters ameliorate the cytotoxic effects of free zinc during infection.