Holden Jeffrey K, Kang Soosung, Hollingsworth Scott A, Li Huiying, Lim Nathan, Chen Steven, Huang He, Xue Fengtian, Tang Wei, Silverman Richard B, Poulos Thomas L
Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences and Chemistry, University of California , 2206 Nat. Sci. 1, Irvine, California 92697-3900, United States.
J Med Chem. 2015 Jan 22;58(2):994-1004. doi: 10.1021/jm501723p. Epub 2015 Jan 6.
Inhibition of bacterial nitric oxide synthase (bNOS) has the potential to improve the efficacy of antimicrobials used to treat infections by Gram-positive pathogens Staphylococcus aureus and Bacillus anthracis. However, inhibitor specificity toward bNOS over the mammalian NOS (mNOS) isoforms remains a challenge because of the near identical NOS active sites. One key structural difference between the NOS isoforms is the amino acid composition of the pterin cofactor binding site that is adjacent to the NOS active site. Previously, we demonstrated that a NOS inhibitor targeting both the active and pterin sites was potent and functioned as an antimicrobial ( Holden , , Proc. Natl. Acad. Sci. U.S.A. 2013 , 110 , 18127 ). Here we present additional crystal structures, binding analyses, and bacterial killing studies of inhibitors that target both the active and pterin sites of a bNOS and function as antimicrobials. Together, these data provide a framework for continued development of bNOS inhibitors, as each molecule represents an excellent chemical scaffold for the design of isoform selective bNOS inhibitors.
抑制细菌一氧化氮合酶（bNOS）有可能提高用于治疗革兰氏阳性病原体金黄色葡萄球菌和炭疽芽孢杆菌感染的抗菌药物的疗效。然而，由于一氧化氮合酶（NOS）活性位点几乎相同，抑制剂对bNOS相对于哺乳动物NOS（mNOS）同工型的特异性仍然是一个挑战。NOS同工型之间的一个关键结构差异是与NOS活性位点相邻的蝶呤辅因子结合位点的氨基酸组成。此前，我们证明了一种同时靶向活性位点和蝶呤位点的NOS抑制剂具有强效，并具有抗菌作用（霍尔登等人，《美国国家科学院院刊》，2013年，第110卷，第18127页）。在此，我们展示了针对bNOS活性位点和蝶呤位点并具有抗菌作用的抑制剂的更多晶体结构、结合分析和细菌杀伤研究。这些数据共同为bNOS抑制剂的持续开发提供了一个框架，因为每个分子都代表了设计同工型选择性bNOS抑制剂的优秀化学支架。
