**Highlights**


Tuberculosis (TB) has been, and continues to be a global health threat, and remains the leading cause of death due to a single infectious agent (*M. tuberculosis*), having claimed ~1.4 million lives in 2019 alone [1]. In the past 2 years, the Covid-19 pandemic has further exacerbated the threat of TB mainly due to a decrease in TB case detection, with trajectories predicting an increase of ~1 million additional

new cases per year from 2020 to 2025 [1]. Furthermore, considering the increasing prevalence of drug resistant (DR) (Rif resistant-RR, multidrug resistant-MDR, and extensively drug resistant- XDR) forms of TB infections, the need for more effective treatment strategies has not been direr. The current standard treatment regimen for drug-susceptible (DS) TB has been in use for decades and includes a combination of four drugs: isoniazid (Inh), rifampicin (Rif), ethambutol (Emb) and pyrazinamide (Pza) for 2 months and a further 4 months of only Inh and Rif (**Figure 1** [2, 3]). The treatment of DR-TB is more complicated and can take up to 18 months, depending on the resistance profile of the infection. Although available, several challenges are faced during the treatment of TB disease. Most notable is the duration and complexity of treatment, toxicity and in the case of HIV-TB coinfection, the possible adverse interactions between anti-TB drugs and antiretrovirals. Despite these challenges, treatment success rates of 85% and 57% have been reported for DS- and DR-TB respectively in 2019 [1]; however, these will not be sufficient to meet the milestones setup as part of the End TB Strategy which include a 90% reduction in incidence rates and 95% reduction in mortality by 2035 compared to 2015 [4]. Optimization and implementation of innovative tools including new drug and treatment regimens are predicted to significantly improve this outlook.

The past 20 years have seen considerable progress in the TB drug discovery arena, with 13 new compounds currently in clinical trials (https://www.newtbdrugs. org/pipeline/clinical). The highlights of TB drug discovery include Bedaquiline (Bdq), Delamanid and, most recently, Pretomanid (PA-824). Within the last 9 years, these were the first three new drugs to be approved for the treatment of TB since the discovery of Rif in the 1960's. Although currently only approved for the treatment of

**Figure 1.** *Current drugs used for the treatment of TB. Adapted from [2, 3] (CC BY 2.0).*

#### *Drug Repurposing for Tuberculosis DOI: http://dx.doi.org/10.5772/intechopen.101393*

DR-TB, both Bdq and PA-824 are being tested as part of novel combination regimens for the treatment of DS-TB. Further highlighting the progress of the TB drug discovery field, the pre-clinical pipeline is also rich in new compounds.

The current scope of the drug discovery and development pipeline is promising; however, the development of a novel drug is a complicated, laborious, and expensive endeavour. From initial screening to clinical usage, the development of a new compound can take up to 15 years and cost more than \$1 billion (**Figure 2**) [5, 6]. In addition, there is a high attrition rate of hit compounds during the discovery cascade and clinical trials, further adding to the difficulty of getting novel antimicrobials into the clinic [5–7]. To overcome some of the challenges faced during conventional drug discovery programs, a strategy that has been gaining more interest in recent years is "Drug Repurposing".

Drug repurposing is the process of identifying novel uses of existing drugs for the treatment of disease outside of the scope of the original medical indication. It is also referred to as drug repositioning, redirecting, re-tasking, reprofiling or recycling [8, 9]. This strategy offers several advantages over a conventional drug discovery approach, including (i) reduced risk of failure, (ii) quicker development times, (iii) less investment and lower average costs, and (iv) the possibility of identifying new targets and/or pathways for further investigation (**Figure 2**) [8–10]. Drug repurposing has been successfully applied to several diseases and conditions including HIV, cancer and arthritis [9]. While offering notable advantages over a conventional approach, candidate compounds discovered via drug repurposing are still subject to regulatory requirements prior to therapeutic implementation. These requirements include compound acquisition and licencing, development/optimization for the new application via clinical trials and registration with the relevant regulatory bodies (**Figure 2**).

Repurposing is not new to the treatment of TB. The backbone of the current regimen, Rif, belongs to the rifamycin group of antibiotics [11]. Rifamycins were originally developed for broad-spectrum antibacterial activity and through structure–activity relationship studies, was shown to have the greatest growth inhibitory effect against mycobacteria [11, 12]. The mechanism of action (MoA) of rifamycins involves the inhibition of DNA-dependent RNA polymerase, thus interfering with

#### **Figure 2.**

*A comparison of the time taken to get into the clinic when using a traditional drug discovery approach versus a drug repurposing approach. ADMET: Absorption, distribution, metabolism, excretion and toxicity. Adapted from [5].*

transcription. While the main application is for DS-TB, Rif has also been used for other bacterial infections e.g. treatment of staphylococcal endocarditis, eradication of group A beta-hemolytic streptococci from pharyngeal carriages and as prophylaxis for close contacts of paediatric patients with *Haemophilus influenzae* or *Neisseria meningitidis* infections [13]. In recent years, drug repurposing has once again gained traction for novel TB treatments, evidenced by 6 different repurposed drugs currently being evaluated in Phase II or III clinical trials [1]. Following an analysis of the published literature related to drug repurposing for TB, the repurposed drugs that are currently in the pre-clinical and clinical pipeline, their molecular mechanisms and therapeutic applications will be discussed further.

### **2. State of the art**

In order to assess what the current scientific field entails, a network analysis was conducted from the Web of Science database (All Databases) using the search terms: repurpose\* (repurposed, repurposing), tuberculosis and drug\* (drugs). A total of 424 publications were identified within the search criteria and it is evident from **Figure 3** that there has been an increase in research involved with the repurposing of old drugs in the fight against TB. In 2020, 77 manuscripts were published related to this topic, and this is expected to further increase in 2021. Additionally, VOS viewer, was used to assess specific keywords within the total number of publications (https://www.vosviewer.com/). The co-occurrences of all keywords were counted using a full counting method. The minimum keyword occurrence was set to three and out of the 416 identified keywords, 35 met the selection criteria. The third most occurring keyword, after "*M. tuberculosis*" and "Tuberculosis", was "*in vitro*", which indicates that this field of enquiry is still at an early stage (**Figure 4**). This is reiterated by the increase in publications on repurposing in recent years (**Figure 3**) as well as the identification of "drug repositioning" in **Figure 5**. Interestingly, the only drug that satisfied the selection criteria was thioridazine, an antipsychotic drug. It would be expected that additional repurposed drugs will occupy this space as more data becomes available and clinical trials are completed.

#### **Figure 3.**

*A steady incline in recent years of the number of scientific articles, related to the search topic "repurposing drugs for tuberculosis". The bars represent the number of published articles according to year. The year 2020 accounts for 18.2% of the published articles related to this topic. (web of science (https://www.webofknowledge.com)).*

*Drug Repurposing for Tuberculosis DOI: http://dx.doi.org/10.5772/intechopen.101393*

#### **Figure 4.**

*Bibliographic network analysis of the keywords in published scientific articles, using the search terms "repurposing drugs for tuberculosis" (web of science – All databases). The circles indicate 35 of the most re-occurring keywords, while the size of the circles represents the importance of the keyword. The lines represent the interconnectivity of the keywords (www.vosviewer.com).*

#### **Figure 5.**

*A time-correlation analysis of the published material related to the search terms. An increase in articles mentioning "drug repurposing", "host-directed therapies" and "adjunctive therapy" can be seen. A trend towards computational approaches, including "docking" is also evident (www.vosviewer.com).*
