Center for Biophysics and Computational Biology, University of Illinois, Urbana, IL 61801, USA.
Proc Natl Acad Sci U S A. 2013 Jan 2;110(1):123-8. doi: 10.1073/pnas.1219899110. Epub 2012 Dec 17.
With the rise in resistance to antibiotics such as methicillin, there is a need for new drugs. We report here the discovery and X-ray crystallographic structures of 10 chemically diverse compounds (benzoic, diketo, and phosphonic acids, as well as a bisamidine and a bisamine) that inhibit bacterial undecaprenyl diphosphate synthase, an essential enzyme involved in cell wall biosynthesis. The inhibitors bind to one or more of the four undecaprenyl diphosphate synthase inhibitor binding sites identified previously, with the most active leads binding to site 4, outside the catalytic center. The most potent leads are active against Staphylococcus aureus [minimal inhibitory concentration (MIC)(90) ∼0.25 µg/mL], and one potently synergizes with methicillin (fractional inhibitory concentration index = 0.25) and is protective in a mouse infection model. These results provide numerous leads for antibacterial development and open up the possibility of restoring sensitivity to drugs such as methicillin, using combination therapies.
随着耐甲氧西林等抗生素的出现，我们需要开发新的药物。我们在此报告了 10 种具有化学多样性的化合物（苯甲酸、二酮酸和膦酸，以及双脒和双胺）的发现和 X 射线晶体结构，这些化合物抑制了细菌十一碳烯二磷酸合酶，这是一种参与细胞壁生物合成的必需酶。抑制剂结合到以前鉴定的四个十一碳烯二磷酸合酶抑制剂结合位点中的一个或多个位点，最活跃的先导化合物结合到位于催化中心之外的第四位点。最有效的先导化合物对金黄色葡萄球菌具有活性（最小抑菌浓度（MIC）（90）为∼0.25μg/mL），与甲氧西林（部分抑菌浓度指数= 0.25）强烈协同作用，并在小鼠感染模型中具有保护作用。这些结果为抗菌药物的开发提供了许多先导化合物，并为使用联合疗法恢复对药物（如甲氧西林）的敏感性开辟了可能性。
