Pharmacologically active metabolites, combination screening and target identification-driven drug repositioning in antituberculosis drug discovery Elizabeth M. Kigondu a,b , Antonina Wasuna a,b , Digby F. Warner c,d,⇑ , Kelly Chibale a,b,c,⇑ a Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa b South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa c Institute of Infectious Disease & Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa d 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 article info Article history: Received 6 March 2014 Revised 4 June 2014 Accepted 6 June 2014 Available online 16 June 2014 Keywords: Chlorpromazine Active metabolites Fusidic acid Host permeation Drug repositioning Drug repurposing abstract There has been renewed interest in alternative strategies to address bottlenecks in antibiotic develop- ment. 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 permeabil- ity in an organism that poses a special challenge to new drug development. Ó 2014 Elsevier Ltd. All rights reserved. 1. Introduction Tuberculosis (TB) is a global problem: there were around 8.6 million new cases in 2012, with the disease claiming approxi- mately 1.3 million lives. 1 Moreover, it is estimated that one-third of the world’s population (approximately 2 billion people) is infected with the causative agent, Mycobacterium tuberculosis. 2 There are a number of endemic regions which carry the greatest burden of disease: of these, South Africa ranks third behind only the world’s most populous countries, India and China. By far the largest proportion (approximately 80%) of HIV-positive incident TB cases are in Africa, with South Africa, which has only 0.7% of the world’s population, contributing a huge portion of these at 25% of all HIV-TB co-infections. 3–5 In addition to HIV, multiple factors continue to undermine TB control measures in endemic areas, including the increasing emergence of multi-drug resistant (MDR) and extensively-drug resistant (XDR) M. tuberculosis strains that are resistant to the major anti-tubercular agents, the variable availability and inconsistent quality of the frontline anti-TB drugs, the prevalence of other chronic diseases that can increase TB mor- bidity, and numerous sociological confounders. 6 Although a vac- cine exists, the widely administered BCG is effective only against the most severe forms of pediatric TB disease and, critically, offers no protection against adult pulmonary TB. 7 Instead, the major thrust of global control efforts is devoted to chemotherapeutic intervention in active disease, utilizing a combination therapy that extends over a minimum six-month treatment period comprising a two-month intensive phase with four drugs and a four-month con- tinuation phase with two drugs. 8 For MDR-TB, the treatment dura- tion is extended to a minimum of 9-12 months, and utilizes drug combinations that are less easily administered, less well tolerated, more expensive, and carry a much higher risk of failure. XDR-TB and, more recently, totally drug resistant (TDR)-TB pose an even greater therapeutic challenge, and can be almost untreatable. 9 For a disease that ranks behind HIV only in mortality owing to a single infectious agent, it is sobering that the majority of the drugs used to treat TB were developed 50–60 years ago. 6 Recent years have witnessed a massive shift, however, and new drug discovery http://dx.doi.org/10.1016/j.bmc.2014.06.012 0968-0896/Ó 2014 Elsevier Ltd. All rights reserved. ⇑ Corresponding authors. Tel.: +27 214066556 (D.F.W.), +27 216502553 (K.C.). E-mail addresses: Digby.Warner@uct.ac.za (D.F. Warner), Kelly.Chibale@uct.ac.za (K. Chibale). Bioorganic & Medicinal Chemistry 22 (2014) 4453–4461 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc