title: Pharmacologically active metabolites, combination screening and target identification-driven drug repositioning in antituberculosis drug discovery.
abstract: 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.
authors.affiliation: 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.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Kigondu
authors.affiliation: 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.
authors.forename: Antonina
authors.initials: A
authors.lastname: Wasuna
authors.affiliation: 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. Electronic address: Digby.Warner@uct.ac.za.
authors.forename: Digby F
authors.initials: DF
authors.lastname: Warner
authors.affiliation: 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. Electronic address: Kelly.Chibale@uct.ac.za.
authors.forename: Kelly
authors.initials: K
authors.lastname: Chibale
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D055808:Drug Discovery; D005672:Fusidic Acid / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D005672:Fusidic Acid
keywords: Active metabolites; Chlorpromazine; Drug repositioning; Drug repurposing; Fusidic acid; Host permeation