Arundhati Maitra

Repurposing — a ray of hope in tackling extensively drug resistance in tuberculosis

Tuberculosis (TB) remains a serious concern more than two decades on from when the World Health Organization declared it a global health emergency. The alarming rise of antibiotic resistance in Mycobacterium tuberculosis, the etiological agent of TB, has made it exceedingly difficult to control the disease with the existing portfolio of anti-TB chemotherapy. The development of effective drugs with novel mechanism(s) of action is thus of paramount importance to tackle drug resistance. The development of novel chemical entities requires more than 10 years of research, requiring high-risk investment to become commercially available. Repurposing pre-existing drugs offers a solution to circumvent this mammoth investment in time and funds. In this context, several drugs with known safety and toxicity profiles have been evaluated against the TB pathogen and found to be efficacious against its different physiological states. As the endogenous targets of these drugs in the TB bacillus are most likely to be novel, there is minimal chance of cross-resistance with front-line anti-TB drugs. Also, reports that some of these drugs may potentially have multiple targets means that the possibility of the development of resistance against them is minimal. Thus repurposing existing molecules offers immense promise to tackle extensively drug-resistant TB infections.

Design and Synthesis of 1-((1,5-Bis(4-chlorophenyl)-2-methyl-1H-pyrrol-3-yl)methyl)-4-methylpiperazine (BM212) and N-Adamantan-2-yl-N'-((E)-3,7-dimethylocta-2,6-dienyl)ethane-1,2-diamine (SQ109) Pyrrole Hybrid Derivatives: Discovery of Potent Antitubercular Agents Effective against Multidrug-Resistant Mycobacteria

Novel pyrroles have been designed, synthesized, and evaluated against mycobacterial strains. The pyrroles have originally been designed as hybrids of the antitubercular drugs BM212 (1) and SQ109 (2), which showed common chemical features with very similar topological distribution. A perfect superposition of the structures of 1 and 2 revealed by computational studies suggested the introduction of bulky substituents at the terminal portion of the pyrrole C3 side chain and the removal of the C5 aryl moiety. Five compounds showed high activity toward Mycobacterium tuberculosis, while 9b and 9c were highly active also against multidrug-resistant clinical isolates. Compound 9c showed low eukaryotic cell toxicity, turning out to be an excellent lead candidate for preclinical trials. In addition, four compounds showed potent inhibition (comparable to that of verapamil) toward the whole-cell drug efflux pump activity of mycobacteria, thus turning out to be promising multidrug-resistance-reversing agents.

HT-SPOTi: A Rapid Drug Susceptibility Test (DST) to Evaluate Antibiotic Resistance Profiles and Novel Chemicals for Anti-Infective Drug Discovery.

Antibiotic resistance is one of the major threats to global health and well‐being. The past decade has seen an alarming rise in the evolution and spread of drug‐resistant strains of pathogenic microbes. The emergence of extensively drug resistant (XDR) strains of Mycobacterium tuberculosis and antimicrobial resistance among the ESKAPE ( E nterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and E nterobacter species) as well as fungal pathogens (such as certain species of Candida, Aspergillus, Cryptococcus, and Trichophyton) poses a significant 21st century scientific challenge. With an extremely limited arsenal of efficacious antibiotics, techniques that can (a) identify novel antimicrobials and (b) detect antimicrobial resistance are becoming increasingly important. In this article, we illustrate the HT‐SPOTi, an assay that is principally based on the growth of an organism on agar medium containing a range of different concentrations of drugs or inhibitors. The simple methodology makes this assay ideal for evaluating novel antimicrobial compounds as well as profiling an organisms antibiotic resistance profile.

Repurposing drugs for treatment of tuberculosis: a role for non-steroidal anti-inflammatory drugs

INTRODUCTION The number of cases of drug-resistant Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), has risen rapidly in recent years. This has led to the resurgence in repurposing existing drugs, such as non-steroidal anti-inflammatory drugs (NSAIDs), for anti-TB treatment. SOURCES OF DATA Evidence from novel drug screening in vitro, in vivo, pharmacokinetic/pharmacodynamics analyses and clinical trials has been used for the preparation of this systematic review of the potential of NSAIDs for use as an adjunct in new TB chemotherapies. AREAS OF AGREEMENT Certain NSAIDs have demonstrated inhibitory properties towards actively replicating, dormant and drug-resistant clinical isolates of M. tuberculosis cells. AREAS OF CONTROVERSY NSAIDs are a diverse class of drugs, which have reported off-target activities, and their endogenous antimicrobial mechanism(s) of action is still unclear. GROWING POINTS It is essential that clinical trials of NSAIDs continue, in order to assess their suitability for addition to the current TB treatment regimen. Repurposing molecules such as NSAIDs is a vital, low-risk strategy to combat the trend of rapidly increasing antibiotic resistance.

The draft genome of Mycobacterium aurum, a potential model organism for investigating drugs against Mycobacterium tuberculosis and Mycobacterium leprae

Mycobacterium aurum (M. aurum) is an environmental mycobacteria that has previously been used in studies of anti-mycobacterial drugs due to its fast growth rate and low pathogenicity. The M. aurum genome has been sequenced and assembled into 46 contigs, with a total length of 6.02Mb containing 5684 annotated protein-coding genes. A phylogenetic analysis using whole genome alignments positioned M. aurum close to Mycobacterium vaccae and Mycobacterium vanbaalenii, within a clade related to fast-growing mycobacteria. Large-scale genomic rearrangements were identified by comparing the M. aurum genome to those of Mycobacterium tuberculosis and Mycobacterium leprae. M. aurum orthologous genes implicated in resistance to anti-tuberculosis drugs in M. tuberculosis were observed. The sequence identity at the DNA level varied from 68.6% for pncA (pyrazinamide drug-related) to 96.2% for rrs (streptomycin, capreomycin). We observed two homologous genes encoding the catalase-peroxidase enzyme (katG) that is associated with resistance to isoniazid. Similarly, two embB homologues were identified in the M. aurum genome. In addition to describing for the first time the genome of M. aurum, this work provides a resource to aid the use of M. aurum in studies to develop improved drugs for the pathogenic mycobacteria M. tuberculosis and M. leprae.

TB Summit 2014: prevention, diagnosis, and treatment of tuberculosis-a meeting report of a Euroscicon conference.

World TB Day commemorates Dr Robert Koch’s first announcement on March 24, 1882, that the bacterium Mycobacterium tuberculosis is the causative agent of tuberculosis. Currently, the event comprises of several conferences, meetings and activities held all over the world with the singular intention of raising public awareness about the global health emergency. In spite of having discovered the etiological agent of tuberculosis more than a century ago, a sizeable population still contract the disease every year and fall prey to it. In 2012, an estimated 8.6 million people developed the disease with 1.3 million succumbing to it. The number of TB deaths in children is unacceptably large, given that most are preventable. However, the challenge appears to be shifting toward attempts to control the rise and spread of the drug resistant variants of the microbe. To achieve this, a concerted effort from academia, clinical practice, and industry has been put forth. The TB Summit 2014 attempted to raise awareness as well as bring together experts involved in different aspects of tuberculosis research to help establish a more collective approach to battle this age-old disease.

Nano-Formulation of Ethambutol with Multifunctional Graphene Oxide and Magnetic Nanoparticles Retains Its Anti-Tubercular Activity with Prospects of Improving Chemotherapeutic Efficacy

Tuberculosis (TB) is a dreadful bacterial disease, infecting millions of human and cattle every year worldwide. More than 50 years after its discovery, ethambutol continues to be an effective part of the World Health Organization’s recommended frontline chemotherapy against TB. However, the lengthy treatment regimens consisting of a cocktail of antibiotics affect patient compliance. There is an urgent need to improve the current therapy so as to reduce treatment duration and dosing frequency. In this study, we have designed a novel anti-TB multifunctional formulation by fabricating graphene oxide with iron oxide magnetite nanoparticles serving as a nano-carrier on to which ethambutol was successfully loaded. The designed nanoformulation was characterised using various analytical techniques. The release of ethambutol from anti-TB multifunctional nanoparticles formulation was found to be sustained over a significantly longer period of time in phosphate buffer saline solution at two physiological pH (7.4 and 4.8). Furthermore, the nano-formulation showed potent anti-tubercular activity while remaining non-toxic to the eukaryotic cells tested. The results of this in vitro evaluation of the newly designed nano-formulation endorse its further development in vivo.

Novel Anti-Tuberculosis Nanodelivery Formulation of Ethambutol with Graphene Oxide

Tuberculosis (TB) is a bacterial disease responsible for millions of infections and preventable deaths each year. Its treatment is complicated by patients’ noncompliance due to dosing frequency, lengthy treatment, and adverse side effects associated with current chemotherapy. However, no modifications to the half-a-century old standard chemotherapy have been made based on a nanoformulation strategy to improve pharmacokinetic efficacy. In this study, we have designed a new nanodelivery formulation, using graphene oxide as the nanocarrier, loaded with the anti-TB antibiotic, ethambutol. The designed formulation was characterized using a number of molecular analytical techniques. It was found that sustained release of the drug resulted in better bioavailability. In addition, the designed formulation demonstrated high biocompatibility with mouse fibroblast cells. The anti-TB activity of the nanodelivery formulation was determined using whole-cell resazurin microtiter plate assay, modified-spot culture growth inhibition assay, and biofilm inhibition assay. The nanodelivery formulation showed good anti-mycobacterial activity. The anti-mycobacterial activity of Ethambutol was unaffected by the drug loading and release process. The results of this study demonstrated the potential of this new nanodelivery formulation strategy to be considered for modifying existing chemotherapy to yield more efficacious antibiotic treatment against TB.

Tetrahydroisoquinolines affect the whole-cell phenotype of Mycobacterium tuberculosis by inhibiting the ATP-dependent MurE ligase

Objectives (S)-Leucoxine, isolated from the Colombian Lauraceae tree Rhodostemonodaphne crenaticupula Madriñan, was found to inhibit the growth of Mycobacterium tuberculosis H37Rv. A biomimetic approach for the chemical synthesis of a wide array of 1-substituted tetrahydroisoquinolines was undertaken with the aim of elucidating a common pharmacophore for these compounds with novel mode(s) of anti-TB action. Methods Biomimetic Pictet–Spengler or Bischler–Napieralski synthetic routes were employed followed by an evaluation of the biological activity of the synthesized compounds. Results In this work, the synthesized tetrahydroisoquinolines were found to inhibit the growth of M. tuberculosis H37Rv and affect its whole-cell phenotype as well as the activity of the ATP-dependent MurE ligase, a key enzyme involved in the early stage of cell wall peptidoglycan biosynthesis. Conclusions As the correlation between the MIC and the half-inhibitory enzymatic concentration was not particularly strong, there is a credible possibility that these compounds have pleiotropic mechanism(s) of action in M. tuberculosis.

Synthesis and SAR evaluation of novel thioridazine derivatives active against drug-resistant tuberculosis.

The neuroleptic drug thioridazine has been recently repositioned as possible anti-tubercular drug. Thioridazine showed anti-tubercular activity against drug resistant mycobacteria but it is endowed with adverse side effects. A small library of thioridazine derivatives has been designed through the replacement of the piperidine and phenothiazine moieties, with the aim to improve the anti-tubercular activity and to reduce the cytotoxic effects. Among the resulting compounds, the indole derivative 12e showed an antimycobacterial activity significantly better than thioridazine and a cytotoxicity 15-fold lower.