Nitric Oxide Synthase as a Target for Methicillin-Resistant Staphylococcus aureus
Nitric Oxide Synthase as a Target for Methicillin-Resistant Staphylococcus aureus
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DOI：
10.1016/j.chembiol.2015.05.013
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发表时间：
2015-06-18
影响因子：
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通讯作者：
Poulos, Thomas L.
中科院分区：
文献类型：
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作者：
Holden, Jeffrey K.;Kang, Soosung;Poulos, Thomas L.
与耐甲氧西林金黄色葡萄球菌（MRSA）相关的细菌感染是医院的主要经济负担，并且在感染者中赋予高发病率和死亡率。因此，有必要开发新的治疗靶点来对抗这种危险的病原体。在这里，我们报告的鉴定和表征，包括晶体结构，两个一氧化氮合酶（NOS）抑制剂，作为抗微生物对MRSA的功能。这些数据提供了细菌NOS（bNOS）抑制剂可以与氧化应激协同作用以增强MRSA杀灭的第一个证据。晶体结构显示，每种抑制剂接触bNOS中的活性位点Ile残基，其为哺乳动物NOS同种型中的瓦尔。突变研究表明，bNOS中Ile提供的额外非极性接触有助于与细菌酶更紧密地结合。
Bacterial infections associated withmethicillin-resistant Staphylococcus aureus (MRSA) are a major economic burden to hospitals, and confer high rates of morbidity and mortality among those infected. Exploitation of novel therapeutic targets is thus necessary to combat this dangerous pathogen. Here, we report on the identification and characterization, including crystal structures, of two nitric oxide synthase (NOS) inhibitors that function as anti-microbials against MRSA. These data provide the first evidence that bacterial NOS (bNOS) inhibitors can work synergistically with oxidative stress to enhance MRSA killing. Crystal structures show that each inhibitor contacts an active site Ile residue in bNOS that is Val in the mammalian NOS isoforms. Mutagenesis studies show that the additional nonpolar contacts provided by the Ile in bNOS contribute to tighter binding toward the bacterial enzyme.