2Receptor Specific Ligand conjugated Nanocarriers: an Effective Strategy for Targeted Therapy of Tuberculosis

: Tuberculosis (TB) is an ancient chronic disease caused by the bacillus Mycobacterium tuberculosis, which has affected mankind for more than 4,000 years. Compliance with the standard conventional treatment can assure recovery from tuberculosis, but emergence of drug resistant strains pose a great challenge for effective management of tuberculosis. The process of discovery and development of new therapeutic entities with better specificity and efficacy is unpredictable and time consuming. Hence, delivery of pre-existing drugs with improved targetability is the need of the hour. Enhanced delivery and targetability can ascertain improved bioavailability, reduced toxicity, decreased frequency of dosing and therefore better patient compliance. Nanoformulations are being explored for effective delivery of therapeutic agents, however optimum specificity is not guaranteed. In order to achieve specificity, ligands specific to receptors or cellular components of macrophage and Mycobacteria can be conjugatedto nanocarriers. This approach can improve localization of existing drug molecules at the intramacrophageal site where the parasites reside, improve targeting to the unique cell wall structure of Mycobacterium or improve adhesion to epithelial surface of intestine or alveolar tissue (lectins). Present review focuses on the investigation of various ligands like Mannose, Mycolic acid, Lectin, Aptamers etc. installed nanocarriers that are being envisaged for targeting antitubercular drugs.

Linezolid-Associated Posterior Reversible Leuco-encephalopathy Syndrome in a Patient with Disseminated Tuberculosis

Neurological side-effects of linezolid manifesting as a posterior reversible leuco-encephalopathy syndrome (PRES) is rare. Early identification of this offending drug might reverse this catastrophic event. We report a 45-year-old female, who was diagnosed as a case of disseminated tuberculosis and was treated with antitubercular drugs (ATT), but later developed ATT-induced hepatitis. She was then put on modified ATT (moxifloxacin, terizidone, and linezolid). In the next two days she developed an altered sensorium. Brain imaging was suggestive of PRES. Linezolid was withdrawn, following which she showed an excellent clinical and radiological recovery.

Structure of the ATP synthase from Mycobacterium smegmatis provides targets for treating tuberculosis

The structure has been determined by electron cryomicroscopy of the adenosine triphosphate (ATP) synthase from Mycobacterium smegmatis. This analysis confirms features in a prior description of the structure of the enzyme, but it also describes other highly significant attributes not recognized before that are crucial for understanding the mechanism and regulation of the mycobacterial enzyme. First, we resolved not only the three main states in the catalytic cycle described before but also eight substates that portray structural and mechanistic changes occurring during a 360° catalytic cycle. Second, a mechanism of auto-inhibition of ATP hydrolysis involves not only the engagement of the C-terminal region of an α-subunit in a loop in the γ-subunit, as proposed before, but also a “fail-safe” mechanism involving the b′-subunit in the peripheral stalk that enhances engagement. A third unreported characteristic is that the fused bδ-subunit contains a duplicated domain in its N-terminal region where the two copies of the domain participate in similar modes of attachment of the two of three N-terminal regions of the α-subunits. The auto-inhibitory plus the associated “fail-safe” mechanisms and the modes of attachment of the α-subunits provide targets for development of innovative antitubercular drugs. The structure also provides support for an observation made in the bovine ATP synthase that the transmembrane proton-motive force that provides the energy to drive the rotary mechanism is delivered directly and tangentially to the rotor via a Grotthuss water chain in a polar L-shaped tunnel.

Multiple acyl-CoA dehydrogenase deficiency kills Mycobacterium tuberculosis in vitro and during infection

The human pathogen Mycobacterium tuberculosis depends on host fatty acids as a carbon source. However, fatty acid β-oxidation is mediated by redundant enzymes, which hampers the development of antitubercular drugs targeting this pathway. Here, we show that rv0338c, which we refer to as etfD, encodes a membrane oxidoreductase essential for β-oxidation in M. tuberculosis. An etfD deletion mutant is incapable of growing on fatty acids or cholesterol, with long-chain fatty acids being bactericidal, and fails to grow and survive in mice. Analysis of the mutant’s metabolome reveals a block in β-oxidation at the step catalyzed by acyl-CoA dehydrogenases (ACADs), which in other organisms are functionally dependent on an electron transfer flavoprotein (ETF) and its cognate oxidoreductase. We use immunoprecipitation to show that M. tuberculosis EtfD interacts with FixA (EtfB), a protein that is homologous to the human ETF subunit β and is encoded in an operon with fixB, encoding a homologue of human ETF subunit α. We thus refer to FixA and FixB as EtfB and EtfA, respectively. Our results indicate that EtfBA and EtfD (which is not homologous to human EtfD) function as the ETF and oxidoreductase for β-oxidation in M. tuberculosis and support this pathway as a potential target for tuberculosis drug development.

Adverse Drug Reactions to First-line Anti-tubercular Drugs Based on Individual Case Safety Report in a Single Tertiary Hospital

Background/Aims: Tuberculosis has incidence and mortality rates that are among the highest for all communicable diseases. Adverse drug reactions (ADRs) to anti-tubercular drugs are common, and have a major impact on treatment maintenance and prognosis. It is important to understand the characteristics of ADRs and establish a suitable management plan. Methods: We retrospectively reviewed patients with ADRs during treatment with first-line antitubercular drugs such as isoniazid, rifampicin, ethambutol, and pyrazinamide from 2009 to 2018. Age, sex, and total treatment period, and the onset, severity, seriousness, and system organ class of ADRs, were analyzed to understand the characteristics of first-line anti-tubercular drug-related ADRs. Results: A total of 1,606 of 5,482 patients (29.3%) experienced ADRs after administration of first-line anti-tubercular drugs. The incidence of ADRs related to isoniazid, rifampicin, ethambutol, and pyrazinamide was 22.2%, 21.3%, 24.5%, and 29.6%, respectively. A total of 2,098 ADR reports were made (mean of 1.3 ± 0.6 per patient). The rates of mild, moderate, and severe ADRs were 32.4%, 61.1%, and 6.5%, respectively. There were 127 reports (6.1%) of serious ADRs. Skin and appendage disorders were most frequently reported (27.5%), followed by gastrointestinal disorders (17.5%), and liver and biliary system disorders (13.1%). The total treatment period was longer in patients who experienced ADRs (224.0 ± 3.1 days vs. 247.0 ± 4.7 days, p = 0.009). Conclusions: The incidence of ADRs to first-line anti-tuberculosis drugs was 29.3%, and 6.5% were severe ADRS. ADRs prolonged the overall treatment duration, indicating the importance of their detection and management.

A data compendium of Mycobacterium tuberculosis antibiotic resistance

The Comprehensive Resistance Prediction for Tuberculosis: an International Consortium (CRyPTIC) presents here a global collection of 15,211 Mycobacterium tuberculosis clinical isolates, all of which have undergone whole genome sequencing and have had their minimum inhibitory concentrations to 13 antitubercular drugs measured. The isolates represent five major M. tuberculosis lineages originating from 23 countries across four continents. 6,814 isolates were found resistant to at least one drug, including 2,129 samples fully satisfy the clinical definitions of RR/MDR, pre-XDR or XDR. Resistance status to eight antitubercular drugs can be accurately predicted using a genetic mutation catalogue for over 90% of the isolates. Furthermore, we show the presence of suspected resistance conferring mutations for isolates resistant to the newly introduced drugs bedaquiline, clofazimine, delamanid and linezolid. Finally, a case study of rifampicin mono-resistance is presented to showcase how this compendium could be used to advance our genetic understanding of rare resistance phenotypes and evaluate the likely performance of a widely used molecular diagnostic tool. It is hoped that this compendium, the largest M. tuberculosis matched phenotypic and genotypic dataset to date, will facilitate and inspire new research projects for years to come.

Deep Vein Thrombosis in a Patient of Extrapulmonary Tuberculosis

Among the various complications reported to be caused by tuberculosis (TB), thrombogenic potential is a rare entity. Here, we report a case of colonic tuberculosis in a 30-year-old male who developed left upper limb deep vein thrombosis (DVT). Ruling out other possible causes of DVT and improvement of the affected limb with antitubercular drugs led to conclusion that DVT was most probably due to TB.