Thioridazine for treatment of tuberculosis: Promises and pitfalls Noton K. Dutta a, * , Petros C. Karakousis a, b, * a Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA b Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA Keywords: Mycobacterium tuberculosis Thioridazine Efflux pump inhibitor Adjunctive therapy Latent TB Animal model summary The articles by De Knegt et al. and Singh et al. in a recent issue of this Journal address one of the current debates regarding the potential role of thioridazine in the treatment of tuberculosis. This commentary presents a summary of the available evidence, and, emphasizing the need for further research, asks the question: “How far can we go in repurposing thioridazine?” © 2014 Elsevier Ltd. All rights reserved. 1. Should thioridazine be included in World Health Organization (WHO) group 5 drugs for the treatment of drug- resistant tuberculosis (TB)? Ongoing research has generated several new drugs, which are in various stages of preclinical and clinical assessment [1,2]. Despite this progress [3,4], the global TB drug pipeline is insufficient to address the imminent but unmet medical needs for new anti-TB drugs to treat multidrug-resistant (MDR) and extensively drug- resistant (XDR) TB. Additional sustainable research efforts are also required to identify new drug combinations in order to simplify or shorten TB treatment to 2 months or less, thereby improving medical adherence and preventing new cases of MDR and XDR TB from occurring. Ideally, these new drug regimens should be cost- effective, easily adopted in the field, and have activity in a broad range of individuals, including those with liver compromise (many anti-TB drugs are hepatotoxic), HIV (to avoid drug interactions), and in children (ethambutol and streptomycin may cause permanent defects) [5,6]. Additionally, to minimize the selection of resistant strains, it is highly desirable that the genes encoding the novel drug targets display low mutation frequencies [7]. One strategy for accelerating the discovery of novel regimens is to search for existing compounds, which are in current clinical use for the treatment of other diseases, but which may also exhibit anti- TB properties [8]. Recently, “repurposing” of the old antipsychotic phenothiazine, thioridazine (TRZ) [9], has been considered as an adjunctive therapy for MDR- and XDR-TB cases [9e13]. TRZ has broad-spectrum antibacterial (antimicrobial, non- antibiotic) activity [14e16], including against various drug- sensitive and drug-resistant Mycobacterium spp. at 6e12.5 mg/ml in vitro [17]. However, the MIC against Mycobacterium tuberculosis (Mtb) in macrophages has been reported to be in the range of 0.1e3.6 mg/ml [18,19] due to intracellular concentration of the drug [18]. Thus, clinically acceptable dosing of TRZ in an infected patient might result in an inhibitory effect in situ (within infected macro- phages) similar to that observed in vitro. Unlike the first-line drugs isoniazid, which targets primarily actively multiplying bacilli by inhibiting the mycolic acid synthesis pathway [20,21], and the transcriptional inhibitor rifampin, which targets primarily growth- restricted bacilli [22], TRZ has been shown to target both slowly replicating and logarithmically growing bacilli [23e25] in an in vitro hollow fiber system [26], likely due to its multiple mecha- nisms of action. In this issue of Tuberculosis [27], De Knegt and colleagues showed concentration and time-dependent bactericidal activity for TRZ against both actively-replicating and slowly-replicating Mtb. Furthermore, relatively high concentrations of TRZ showed synergy with isoniazid and rifampin. In the case of isoniazid, this resulted in elimination of mycobacteria and prevention of isoniazid-resistant mutants, consistent with similar findings in a mouse model of TB infection [28]. Previously, Viveiros et al. reported that TRZ enhances the activity of rifampin and streptomycin when used in combina- tion at minimally effective concentrations against clinical strains of poly-drug resistant Mtb [29]. Due to its pleiotropic effects, TRZ may provide strategies for multi-target drug development for combination chemotherapy [30e32]. TRZ appears to act on enzymes involved in fatty acid metabolism, efflux proteins (emrE-encoded), oxido-reductases, and proteins (ndh-encoded) involved in aerobic respiration, which overlap with the targets of conventional anti-TB drugs [30,33,34]. In addition, TRZ targets the Rv3160c-Rv3161c operon, which may be required for the detoxification of TRZ, members of the SigB sigma * Corresponding authors. Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. E-mail addresses: ndutta1@jhmi.edu (N.K. Dutta), petros@jhmi.edu (P.C. Karakousis). Contents lists available at ScienceDirect Tuberculosis journal homepage: http://intl.elsevierhealth.com/journals/tube http://dx.doi.org/10.1016/j.tube.2014.09.001 1472-9792/© 2014 Elsevier Ltd. All rights reserved. Tuberculosis xxx (2014) 1e4 Please cite this article in press as: Dutta NK, Karakousis PC, Thioridazine for treatment of tuberculosis: Promises and pitfalls, Tuberculosis (2014), http://dx.doi.org/10.1016/j.tube.2014.09.001