Hugonnet Jean-Emmanuel, Tremblay Lee W, Boshoff Helena I, Barry Clifton E, Blanchard John S
Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Science. 2009 Feb 27;323(5918):1215-8. doi: 10.1126/science.1167498.
beta-lactam antibiotics are ineffective against Mycobacterium tuberculosis, being rapidly hydrolyzed by the chromosomally encoded blaC gene product. The carbapenem class of beta-lactams are very poor substrates for BlaC, allowing us to determine the three-dimensional structure of the covalent BlaC-meropenem covalent complex at 1.8 angstrom resolution. When meropenem was combined with the beta-lactamase inhibitor clavulanate, potent activity against laboratory strains of M. tuberculosis was observed [minimum inhibitory concentration (MIC(meropenem)) less than 1 microgram per milliliter], and sterilization of aerobically grown cultures was observed within 14 days. In addition, this combination exhibited inhibitory activity against anaerobically grown cultures that mimic the "persistent" state and inhibited the growth of 13 extensively drug-resistant strains of M. tuberculosis at the same levels seen for drug-susceptible strains. Meropenem and clavulanate are Food and Drug Administration-approved drugs and could potentially be used to treat patients with currently untreatable disease.
β-内酰胺类抗生素对结核分枝杆菌无效，会被染色体编码的blaC基因产物迅速水解。碳青霉烯类β-内酰胺是BlaC的非常差的底物，这使我们能够在1.8埃分辨率下确定共价BlaC-美罗培南共价复合物的三维结构。当美罗培南与β-内酰胺酶抑制剂克拉维酸联合使用时，观察到对结核分枝杆菌实验室菌株具有强效活性[最低抑菌浓度（MIC（美罗培南））小于每毫升1微克]，并且在14天内观察到需氧培养物的杀菌作用。此外，这种组合对模拟“持续”状态的厌氧培养物表现出抑制活性，并以与药物敏感菌株相同的水平抑制13株广泛耐药结核分枝杆菌菌株的生长。美罗培南和克拉维酸是美国食品药品监督管理局批准的药物，有可能用于治疗目前无法治疗的疾病的患者。
