Marra Andrea
Pfizer Inc., Groton, Connecticut 06340, USA.
Drugs R D. 2006;7(1):1-16. doi: 10.2165/00126839-200607010-00001.
The antibacterial drug discovery industry is fast losing participants; at the same time it is facing the challenge of developing new antibiotics that are effective against frequently occurring and multiply resistant organisms. One intriguing approach is to target bacterial virulence, and the last decade or so has seen a focus on bacterial pathogenesis along with the development of reagents and strategies that could make this possible. Several processes utilised by a range of bacteria to cause infection may be conserved enough to make attractive targets; indeed it is known that mammalian cells can affect bacterial gene expression and vice versa. Interesting targets involving virulence include type III secretion systems, two-component signal transduction systems, quorum sensing, and biofilm formation. In order to better understand these systems and strategies, investigators have developed novel strategies of their own, involving negative selections, surrogate models of infection, and screens for gene induction and antigenicity. Inhibitors of such targets would be unlikely to adversely affect patients, be cross-resistant to existing therapies, or cause resistance themselves. It might be the case that virulence target-based therapies would not be powerful enough to clear an existing infection alone, but if they are instead considered as adjunct therapy to existing antibiotics, or potentiators of the host immune response, they may show efficacy in a non-traditional way.
抗菌药物研发行业正迅速流失参与者；与此同时，该行业面临着开发新型抗生素的挑战，这些抗生素要能有效对抗常见的多重耐药菌。一种引人关注的方法是针对细菌毒力，在过去十年左右的时间里，人们一直关注细菌致病机制，同时也在开发使这成为可能的试剂和策略。一系列细菌用于引发感染的几个过程可能具有足够的保守性，从而成为有吸引力的靶点；事实上，已知哺乳动物细胞可以影响细菌基因表达，反之亦然。涉及毒力的有趣靶点包括III型分泌系统、双组分信号转导系统、群体感应和生物膜形成。为了更好地理解这些系统和策略，研究人员开发了他们自己的新策略，包括负向选择、感染替代模型以及基因诱导和抗原性筛选。针对此类靶点的抑制剂不太可能对患者产生不利影响，不会对现有疗法产生交叉耐药性，也不会自身导致耐药性。基于毒力靶点的疗法可能不足以单独清除现有的感染，但如果将它们视为现有抗生素的辅助疗法，或宿主免疫反应的增强剂，它们可能会以一种非传统的方式显示出疗效。
