Woodford Neil, Wareham David W
Antibiotic Resistance Monitoring and Reference Laboratory, Centre for Infections, Health Protection Agency, London NW9 5EQ, UK.
J Antimicrob Chemother. 2009 Feb;63(2):225-9. doi: 10.1093/jac/dkn467. Epub 2008 Nov 11.
Resistance to antimicrobial agents undermines our ability to treat bacterial infections. It attracts intense media and political interest and impacts on personal health and costs to health infrastructures. Bacteria have developed resistance to all licensed antibacterial agents, and their ability to become resistant to unlicensed agents is often demonstrated during the development process. Conventional approaches to antimicrobial development, involving modification of existing agents or production of synthetic derivatives, are unlikely to deliver the range or type of drugs that will be needed to meet all future requirements. Although many companies are seeking novel targets, further radical approaches to both antimicrobial design and the reversal of resistance are now urgently required. In this article, we discuss 'antisense' (or 'antigene') strategies to inhibit resistance mechanisms at the genetic level. These offer an innovative approach to a global problem and could be used to restore the efficacy of clinically proven agents. Moreover, this strategy has the potential to overcome critical resistances, not only in the so-called 'superbugs' (methicillin-resistant Staphylococcus aureus, glycopeptide-resistant enterococci and multidrug-resistant strains of Acinetobacter baumannii, and Pseudomonas aeruginosa), but in resistant strains of any bacterial species.
对抗菌药物的耐药性削弱了我们治疗细菌感染的能力。它引起了媒体和政治的高度关注，对个人健康以及卫生基础设施的成本产生影响。细菌已对所有已获许可的抗菌药物产生了耐药性，并且在研发过程中它们对未获许可药物产生耐药性的能力也常常得到证实。传统的抗菌药物研发方法，包括对现有药物进行修饰或生产合成衍生物，不太可能提供满足未来所有需求所需的药物种类或类型。尽管许多公司正在寻找新的靶点，但现在迫切需要对抗菌药物设计和耐药性逆转采取更激进的方法。在本文中，我们讨论在基因水平上抑制耐药机制的“反义”（或“反基因”）策略。这些策略为解决这一全球性问题提供了一种创新方法，可用于恢复临床验证药物的疗效。此外，该策略不仅有可能克服在所谓的“超级细菌”（耐甲氧西林金黄色葡萄球菌、耐糖肽肠球菌以及鲍曼不动杆菌和铜绿假单胞菌的多重耐药菌株）中的关键耐药性，而且还能克服任何细菌物种耐药菌株中的关键耐药性。
