Holden Jeffrey K, Kang Soosung, Beasley Federico C, Cinelli Maris A, Li Huiying, Roy Saurabh G, Dejam Dillon, Edinger Aimee L, Nizet Victor, Silverman Richard B, Poulos Thomas L
Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences, and Chemistry, University of California, Irvine, CA 92697-3900, USA.
Departments of Chemistry and Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, IL 60208-3113, USA.
Chem Biol. 2015 Jun 18;22(6):785-92. doi: 10.1016/j.chembiol.2015.05.013.
Bacterial infections associated with methicillin-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 antimicrobials 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.
与耐甲氧西林金黄色葡萄球菌（MRSA）相关的细菌感染给医院带来了巨大的经济负担，并在感染者中导致了高发病率和死亡率。因此，开发新的治疗靶点对于对抗这种危险病原体至关重要。在此，我们报告了两种一氧化氮合酶（NOS）抑制剂的鉴定和表征，包括晶体结构，这两种抑制剂对MRSA具有抗菌作用。这些数据首次证明细菌NOS（bNOS）抑制剂可与氧化应激协同作用，增强对MRSA的杀灭效果。晶体结构表明，每种抑制剂都与bNOS中的一个活性位点异亮氨酸（Ile）残基接触，而在哺乳动物NOS同工型中该残基为缬氨酸（Val）。诱变研究表明，bNOS中Ile提供的额外非极性接触有助于与细菌酶的结合更紧密。
