Kigondu Elizabeth M, Wasuna Antonina, Warner Digby F, Chibale Kelly
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa; South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa.
Institute of Infectious Disease & Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa; MRC/NHLS/UCT Molecular Mycobacteriology Research Unit and DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Department of Clinical Laboratory Sciences, Faculty of Health Sciences, University of Cape Town, Rondebosch 7701, South Africa.
Bioorg Med Chem. 2014 Aug 15;22(16):4453-61. doi: 10.1016/j.bmc.2014.06.012. Epub 2014 Jun 16.
There has been renewed interest in alternative strategies to address bottlenecks in antibiotic development. These include the repurposing of approved drugs for use as novel anti-infective agents, or their exploitation as leads in drug repositioning. Such approaches are especially attractive for tuberculosis (TB), a disease which remains a leading cause of morbidity and mortality globally and, increasingly, is associated with the emergence of drug-resistance. In this review article, we introduce a refinement of traditional drug repositioning and repurposing strategies involving the development of drugs that are based on the active metabolite(s) of parental compounds with demonstrated efficacy. In addition, we describe an approach to repositioning the natural product antibiotic, fusidic acid, for use against Mycobacterium tuberculosis. Finally, we consider the potential to exploit the chemical matter arising from these activities in combination screens and permeation assays which are designed to confirm mechanism of action (MoA), elucidate potential synergies in polypharmacy, and to develop rules for drug permeability in an organism that poses a special challenge to new drug development.
人们对解决抗生素开发瓶颈的替代策略重新产生了兴趣。这些策略包括将已批准药物重新用于新型抗感染剂，或将其用作药物重新定位的先导物。对于结核病（TB）而言，此类方法尤其具有吸引力，结核病仍然是全球发病和死亡的主要原因，并且越来越多地与耐药性的出现相关。在这篇综述文章中，我们介绍了对传统药物重新定位和再利用策略的改进，即开发基于已证明具有疗效的母体化合物的活性代谢物的药物。此外，我们描述了一种将天然产物抗生素夫西地酸重新定位用于抗结核分枝杆菌的方法。最后，我们考虑了在组合筛选和渗透试验中利用这些活性产生的化学物质的潜力，这些试验旨在确认作用机制（MoA），阐明多药联合使用中的潜在协同作用，并制定对新药开发构成特殊挑战的生物体中药物渗透性的规则。
