Potential anti-TB investigational compounds and drugs with repurposing potential in TB therapy: a conspectus.

The latest WHO report estimates about 1.6 million global deaths annually from TB, which is further exacerbated by drug-resistant (DR) TB and comorbidities with diabetes and HIV. Exiguous dosing, incomplete treatment course, and the ability of the tuberculosis bacilli to tolerate and survive current first-line and second-line anti-TB drugs, in either their latent state or active state, has resulted in an increased prevalence of multidrug-resistant (MDR), extensively drug-resistant (XDR), and totally drug-resistant TB (TDR-TB). Although a better understanding of the TB microanatomy, genome, transcriptome, proteome, and metabolome, has resulted in the discovery of a few novel promising anti-TB drug targets and diagnostic biomarkers of late, no new anti-TB drug candidates have been approved for routine therapy in over 50 years, with only bedaquiline, delamanid, and pretomanid recently receiving tentative regulatory approval. Considering this, alternative approaches for identifying possible new anti-TB drug candidates, for effectively eradicating both replicating and non-replicating Mycobacterium tuberculosis, are still urgently required. Subsequently, several antibiotic and non-antibiotic drugs with known treatment indications (TB targeted and non-TB targeted) are now being repurposed and/or derivatized as novel antibiotics for possible use in TB therapy. Insights gathered here reveal that more studies focused on drug-drug interactions between licensed and potential lead anti-TB drug candidates need to be prioritized. This write-up encapsulates the most recent findings regarding investigational compounds with promising anti-TB potential and drugs with repurposing potential in TB therapy.

Computational and Practical Aspects of Drug Repositioning.

The concept of the hypothesis-driven or observational-based expansion of the therapeutic application of drugs is very seductive. This is due to a number of factors, such as lower cost of development, higher probability of success, near-term clinical potential, patient and societal benefit, and also the ability to apply the approach to rare, orphan, and underresearched diseases. Another highly attractive aspect is that the "barrier to entry" is low, at least in comparison to a full drug discovery operation. The availability of high-performance computing, and databases of various forms have also enhanced the ability to pose reasonable and testable hypotheses for drug repurposing, rescue, and repositioning. In this article we discuss several factors that are currently underdeveloped, or could benefit from clearer definition in articles presenting such work. We propose a classification scheme-drug repositioning evidence level (DREL)-for all drug repositioning projects, according to the level of scientific evidence. DREL ranges from zero, which refers to predictions that lack any experimental support, to four, which refers to drugs approved for the new indication. We also present a set of simple concepts that can allow rapid and effective filtering of hypotheses, leading to a focus on those that are most likely to lead to practical safe applications of an existing drug. Some promising repurposing leads for malaria (DREL-1) and amoebic dysentery (DREL-2) are discussed.

Toward Repositioning Niclosamide for Antivirulence Therapy of Pseudomonas aeruginosa Lung Infections: Development of Inhalable Formulations through Nanosuspension Technology.

Inhaled antivirulence drugs are currently considered a promising therapeutic option to treat Pseudomonas aeruginosa lung infections in cystic fibrosis (CF). We have recently shown that the anthelmintic drug niclosamide (NCL) has strong quorum sensing (QS) inhibiting activity against P. aeruginosa and could be repurposed as an antivirulence drug. In this work, we developed dry powders containing NCL nanoparticles that can be reconstituted in saline solution to produce inhalable nanosuspensions. NCL nanoparticles were produced by high-pressure homogenization (HPH) using polysorbate 20 or polysorbate 80 as stabilizers. After 20 cycles of HPH, all formulations showed similar properties in the form of needle-shape nanocrystals with a hydrodynamic diameter of approximately 450 nm and a zeta potential of -20 mV. Nanosuspensions stabilized with polysorbate 80 at 10% w/w to NCL (T80_10) showed an optimal solubility profile in simulated interstitial lung fluid. T80_10 was successfully dried into mannitol-based dry powder by spray drying. Dry powder (T80_10 DP) was reconstituted in saline solution and showed optimal in vitro aerosol performance. Both T80_10 and T80_10 DP were able to inhibit P. aeruginosa QS at NCL concentrations of 2.5-10 µM. NCL, and these formulations did not significantly affect the viability of CF bronchial epithelial cells in vitro at microbiologically active concentrations (i.e., ≤10 µM). In vivo acute toxicity studies in rats confirmed no observable toxicity of the NCL T80_10 DP formulation upon intratracheal administration at a concentration 100-fold higher than the anti-QS activity concentration. These preliminary results suggest that NCL repurposed in the form of inhalable nanosuspensions has great potential for the local treatment of P. aeruginosa lung infections as in the case of CF patients.

Lost interest for existing compounds: New boosts.

Development of new drugs is typically thought of as a bottom-up endeavor where basic science identifies a target, various strategies are used to generate drugs that stimulate or inhibit the target, the drugs are first tested for safety and efficacy in animals and finally efficacy and safety are evaluated in a well defined clinical development process. However, this is not the only way that new drug products are developed. Many new products come from re-initiating development of discontinued drugs, finding new uses for existing drugs, creating a new product by obtaining marketing approval in expanded territories, obtaining approvals for new formulations or a single isomer of a previously approved racemic drug, converting products from prescription to over-the- counter use or converting folk medicines or vitamins to modern pharmaceuticals. Based on this long and successful history of contributions to modern therapeutics, these alternative sources of new products should not be neglected.

Computational and experimental advances in drug repositioning for accelerated therapeutic stratification.

Drug repositioning is an important component of therapeutic stratification in the precision medicine paradigm. Molecular profiling and more sophisticated analysis of longitudinal clinical data are refining definitions of human diseases, creating needs and opportunities to re-target or reposition approved drugs for alternative indications. Drug repositioning studies have demonstrated success in complex diseases requiring improved therapeutic interventions as well as orphan diseases without any known treatments. An increasing collection of available computational and experimental methods that leverage molecular and clinical data enable diverse drug repositioning strategies. Integration of translational bioinformatics resources, statistical methods, chemoinformatics tools and experimental techniques (including medicinal chemistry techniques) can enable the rapid application of drug repositioning on an increasingly broad scale. Efficient tools are now available for systematic drug-repositioning methods using large repositories of compounds with biological activities. Medicinal chemists along with other translational researchers can play a key role in various aspects of drug repositioning. In this review article, we briefly summarize the history of drug repositioning, explain concepts behind drug repositioning methods, discuss recent computational and experimental advances and highlight available open access resources for effective drug repositioning investigations. We also discuss recent approaches in utilizing electronic health record for outcome assessment of drug repositioning and future avenues of drug repositioning in the light of targeting disease comorbidities, underserved patient communities, individualized medicine and socioeconomic impact.

Toward better drug repositioning: prioritizing and integrating existing methods into efficient pipelines.

Recycling old drugs, rescuing shelved drugs and extending patents' lives make drug repositioning an attractive form of drug discovery. Drug repositioning accounts for approximately 30% of the newly US Food and Drug Administration (FDA)-approved drugs and vaccines in recent years. The prevalence of drug-repositioning studies has resulted in a variety of innovative computational methods for the identification of new opportunities for the use of old drugs. Questions often arise from customizing or optimizing these methods into efficient drug-repositioning pipelines for alternative applications. It requires a comprehensive understanding of the available methods gained by evaluating both biological and pharmaceutical knowledge and the elucidated mechanism-of-action of drugs. Here, we provide guidance for prioritizing and integrating drug-repositioning methods for specific drug-repositioning pipelines.