中国科学家合成抗耐药菌新药
中国科学院上海药物研究所研究人员针对细菌DNA复制机制，设计合成一系列4-胍甲基苯甲酸酯和4-胍甲基苯甲酰胺衍生物，发现其中部分化合物能够选择性地杀灭革兰氏阳性菌（包括多种耐药菌株）。与市售抗生素相比，它们对耐万古霉素的肠球菌和万古霉素中介葡萄球菌的作用与利奈唑胺等同，对耐甲氧西林的金葡球菌的效应与万古霉素类似。这项研究成果最近发表在《中国药理学报》（Acta Pharmacologica Sinica）上。
据这项研究的负责人、国家新药筛选中心主任王明伟介绍，开发一种新型抗生素一般需要10年左右的时间，而一代耐药菌的产生只需两年的时间，抗生素的研制速度远远赶不上耐药菌的传播速度。耐药菌株的迅猛发展已成为与耐多药结核杆菌和艾滋病病毒相并列的、对人类健康构成威胁的三大病原微生物之一。为了应对这一问题，许多医药研究机构把注意力转向新型抗菌药物的开发领域，其中针对细菌DNA复制机制的抗菌药物除了具有较强的杀菌效应外，还能阻断抗药遗传性状的传播。
广泛存在于各类细菌中的蛋白酶In，具有类胰蛋白酶和寡肽酶两个活性中心，其中类胰蛋白酶活性仅周期性地出现在细菌DNA复制即将启动的短暂瞬间，可被人工合成的反式胍甲基环己烷酸抑制。根据这一原理，课题组以反式胍甲基环己烷酸为母核，设计合成了一系列4-胍甲基苯甲酸酯和4-胍甲基苯甲酰胺的衍生物，发现其中部分化合物选择性地对革兰氏阳性菌（包括多种耐药菌株）具有较高的杀灭效果。（来源：健康报 王雪飞）
生物谷推荐原始出处：
（Acta Pharmacologica Sinica），29 (2): 267-277，Wen-yuan YU，Ming-wei WANG
Derivatives of aryl-4-guanidinomethylbenzoate and N-aryl-4-guanidinomethylbenzamide as new antibacterial agents: synthesis and bioactivity1
Wen-yuan YU2, Li-xia YANG2, Jian-shu XIE3, Ling ZHOU2, Xue-yuan JIANG4, De-xu ZHU4, Mutsumi MURAMATSU4, Ming-wei WANG2,5
2The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; 3Shanghai East Best Biopharmaceutical Enterprises Co Ltd, Shanghai 200233, China; 4Department of Biochemistry, Nanjing University, Nanjing 210093, China
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1 Project supported in part by grants from the Ministry of Science and Technology of China (No 2004CB518902) and Shanghai Municipality Government (No 30219228 and 05dz22914). Abstract Aim: The aim of the present study was to design, synthesize, and evaluate novel antibacterial agents, derivatives of aryl-4-guanidinomethylbenzoate and N-aryl-4-guanidinomethylbenzamide. Methods: A total of 44 derivatives of aryl-4-guanidin-omethylbenzoate (series A) and N-aryl-4-guanidinomethylbenzamide (series B) were synthesized and their antibacterial activities were assessed in vitro against a variety of Gram-positive and Gram-negative bacteria by an agar dilution method. Results: Twelve compounds showed potent bactericidal effects against a panel of Gram-positive germs, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), vancomycin-intermediate Staphylococcus aureus (VISA), and methicillin-resistant coagulase-negative staphylococci (MRCNS), with minimum inhibitory concentrations (MIC) ranging between 0.5 and 8 µg/mL, which were comparable to the MIC values of several marketed antibiotics. They exhibited weak or no activity on the Gram-negative bacteria tested. In addition, these compounds displayed high inhibitory activities towards oligopeptidase B of bacterial origin. Conclusion: In comparison with the previously reported MIC values of several known antibiotics, the derivatives of aryl-4-guanidinomethylbenzoate and N-aryl-4-guanidinomethylbenzamide showed comparable in vitro bactericidal activities against VRE and VISA as linezolid. Their growth inhibitory effects on MRSA were similar to vancomycin, but were less potent than linezolid and vancomycin against MRCNS. This class of compounds may have the potential to be developed into narrow spectrum antibacterial agents against certain drug-resistant strains of bacteria.
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