Oldfield Eric, Feng Xinxin
Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, IL 61801, USA.
Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, IL 61801, USA.
Trends Pharmacol Sci. 2014 Dec;35(12):664-74. doi: 10.1016/j.tips.2014.10.007. Epub 2014 Nov 5.
New antibiotics are needed because drug resistance is increasing while the introduction of new antibiotics is decreasing. We discuss here six possible approaches to develop 'resistance-resistant' antibiotics. First, multitarget inhibitors in which a single compound inhibits more than one target may be easier to develop than conventional combination therapies with two new drugs. Second, inhibiting multiple targets in the same metabolic pathway is expected to be an effective strategy owing to synergy. Third, discovering multiple-target inhibitors should be possible by using sequential virtual screening. Fourth, repurposing existing drugs can lead to combinations of multitarget therapeutics. Fifth, targets need not be proteins. Sixth, inhibiting virulence factor formation and boosting innate immunity may also lead to decreased susceptibility to resistance. Although it is not possible to eliminate resistance, the approaches reviewed here offer several possibilities for reducing the effects of mutations and, in some cases, suggest that sensitivity to existing antibiotics may be restored in otherwise drug-resistant organisms.
由于耐药性不断增加而新抗生素的引入却在减少，因此需要新的抗生素。我们在此讨论开发“抗耐药性”抗生素的六种可能方法。首先，单一化合物抑制多个靶点的多靶点抑制剂可能比使用两种新药的传统联合疗法更容易开发。其次，由于协同作用，抑制同一代谢途径中的多个靶点有望成为一种有效的策略。第三，通过顺序虚拟筛选应该有可能发现多靶点抑制剂。第四，重新利用现有药物可产生多靶点治疗药物的组合。第五，靶点不一定是蛋白质。第六，抑制毒力因子形成并增强先天免疫力也可能导致耐药性降低。虽然不可能消除耐药性，但本文综述的方法提供了几种减少突变影响的可能性，并且在某些情况下表明，原本耐药的生物体可能会恢复对现有抗生素的敏感性。
