Unlocking translational machinery for antitubercular drug development.

Targeting translational factor proteins (TFPs) presents significant promise for the development of innovative antitubercular drugs. Previous insights from antibiotic binding mechanisms and recently solved 3D crystal structures of Mycobacterium tuberculosis (Mtb) elongation factor thermo unstable-GDP (EF-Tu-GDP), elongation factor thermo stable-EF-Tu (EF-Ts-EF-Tu), and elongation factor G-GDP (EF-G-GDP) have opened up new avenues for the design and development of potent antituberculosis (anti-TB) therapies.

Development and validation of consensus machine learning-based models for the prediction of novel small molecules as potential anti-tubercular agents.

Tuberculosis (TB) is an infectious disease and the leading cause of death globally. The rapidly emerging cases of drug resistance among pathogenic mycobacteria have been a global threat urging the need of new drug discovery and development. However, considering the fact that the new drug discovery and development is commonly lengthy and costly processes, strategic use of the cutting-edge machine learning (ML) algorithms may be very supportive in reducing both the cost and time involved. Considering the urgency of new drugs for TB, herein, we have attempted to develop predictive ML algorithms-based models useful in the selection of novel potential small molecules for subsequent in vitro validation. For this purpose, we used the GlaxoSmithKline (GSK) TCAMS TB dataset comprising a total of 776 hits that were made publicly available to the wider scientific community through the ChEMBL Neglected Tropical Diseases (ChEMBL-NTD) database. After exploring the different ML classifiers, viz. decision trees (DT), support vector machine (SVM), random forest (RF), Bernoulli Naive Bayes (BNB), K-nearest neighbors (k-NN), and linear logistic regression (LLR), and ensemble learning models (bagging and Adaboost) for training the model using the GSK dataset, we concluded with three best models, viz. Adaboost decision tree (ABDT), RF classifier, and k-NN models that gave the top prediction results for both the training and test sets. However, during the prediction of the external set of known anti-tubercular compounds/drugs, it was realized that each of these models had some limitations. The ABDT model correctly predicted 22 molecules as actives, while both the RF and k-NN models predicted 18 molecules correctly as actives; a number of molecules were predicted as actives by two of these models, while the third model predicted these compounds as inactives. Therefore, we concluded that while deciding the anti-tubercular potential of a new molecule, one should rely on the use of consensus predictions using these three models; it may lessen the attrition rate during the in vitro validation. We believe that this study may assist the wider anti-tuberculosis research community by providing a platform for predicting small molecules with subsequent validation for drug discovery and development.

Targeting the cytochrome bc1 complex for drug development in M. tuberculosis: review.

The terminal oxidases of the oxidative phosphorylation pathway play a significant role in the survival and growth of M. tuberculosis, targeting these components lead to inhibition of M. tuberculosis. Many drug candidates targeting various components of the electron transport chain in M. tuberculosis have recently been discovered. The cytochrome bc1-aa3 supercomplex is one of the most important components of the electron transport chain in M. tuberculosis, and it has emerged as the novel target for several promising candidates. There are two cryo-electron microscopy structures (PDB IDs: 6ADQ and 6HWH) of the cytochrome bc1-aa3 supercomplex that aid in the development of effective and potent inhibitors for M. tuberculosis. In recent years, a number of potential candidates targeting the QcrB subunit of the cytochrome bc1 complex have been developed. In this review, we describe the recently identified inhibitors that target the electron transport chain's terminal oxidase enzyme in M. tuberculosis, specifically the QcrB subunit of the cytochrome bc1 complex.

Management zone delineation and spatial distribution of micronutrients in cold-arid region of India.

The plant health is governed by many factors: soil playing a central role which exhibits huge variability in its characteristics. Micronutrients even though needed in small quantities by plants play an indispensable role in affecting the crop growth and development. The assessment of spatial variability of different soil parameters is incumbent for tackling the loss of crop productivity on account of non-receipt of desirable inputs. The present investigation centered on the spatial distribution of soil parameters and micronutrients was conducted to delineate management zones (MZs) in cold arid region (Kargil) of India for proficient micronutrient management. Overall 454 georeferenced representative soil samples at the depths of 0-15 cm were garnered. The soil samples were processed and analyzed for different soil parameters encompassing pH, EC (electrical conductivity), SOC (soil organic carbon), and available micro-nutrient (iron, manganese, zinc, copper and nickel) concentrations. The distinct variation in the soil properties including micronutrients was identified with coefficient of variation ranging as low as 5.62% to moderate (21.16 to 42.49%) and as high as 159.63%. Semivariogram analysis and ordinary kriging of soil variables under study revealed diverse spatial distribution exhibiting medium to high spatial dependence in the region. PCA (principal component analysis) and K-means clustering were expended for the delineation of MZs. Four principal components (PCs) having eigen values > 1 and accounting for 70% of the total variation were subjected to further analysis. The five potential MZs were demarcated on the basis of K-means cluster performance index, and heterogeneity in parameters was discerned. The results of study corroborate that the spatial variability analysis of different soil parameters for delineation/identification of MZs might be effectually employed for site-specific micronutrient management.

Early onset cerebral amyloid angiopathy following childhood exposure to cadaveric dura.

Amyloid-ß transmission has been described in patients both with and without iatrogenic Creutzfeldt-Jakob disease; however, there is little information regarding the clinical impact of this acquired amyloid-ß pathology during life. Here, for the first time, we describe in detail the clinical and neuroimaging findings in 3 patients with early onset symptomatic amyloid-ß cerebral amyloid angiopathy following childhood exposure to cadaveric dura (by neurosurgical grafting in 2 patients and tumor embolization in a third). Our observations provide further in vivo evidence that cerebral amyloid angiopathy might be caused by transmission of amyloid-ß seeds (prions) present in cadaveric dura and have diagnostic relevance for younger patients presenting with suspected cerebral amyloid angiopathy. Ann Neurol 2019; 1-7 ANN NEUROL 2019;85:284-290.

Intravenous Thrombolysis in Unknown-Onset Stroke: Results From the Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Registry.

BACKGROUND AND PURPOSE: Stroke patients with unknown onset (UKO) are excluded from thrombolytic therapy. We aim to study the safety and efficacy of intravenous alteplase in ischemic stroke patients with UKO of symptoms compared with those treated within 4.5 hours in a large cohort. METHODS: Data were analyzed from 47 237 patients with acute ischemic stroke receiving intravenous tissue-type plasminogen activator in hospitals participating in the Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Registry between 2010 and 2014. Two groups were defined: (1) patients with UKO (n=502) and (2) patients treated within 4.5 hours of stroke onset (n=44 875). Outcome measures were symptomatic intracerebral hemorrhage per Safe Implementation of Treatment in Stroke on the 22 to 36 hours post-treatment neuroimaging and mortality and functional outcome assessed by the modified Rankin Scale at 3 months. RESULTS: Patients in UKO group were significantly older, had more severe stroke at baseline, and longer door-to-needle times than patients in the ≤4.5 hours group. Logistic regression showed similar risk of symptomatic intracerebral hemorrhage (adjusted odds ratio, 1.09; 95% confidence interval, 0.44-2.67) and no significant differences in functional independency (modified Rankin Scale score of 0-2; adjusted odds ratio, 0.79; 95% confidence interval, 0.56-1.10), but higher mortality (adjusted odds ratio, 1.58; 95% confidence interval, 1.04-2.41) in the UKO group compared with the ≤4.5 hours group. Patients treated within 4.5 hours showed reduced disability over the entire range of modified Rankin Scale compared with the UKO group (common adjusted odds ratio, 1.29; 95% confidence interval, 1.01-1.65). CONCLUSIONS: Our data suggest no excess risk of symptomatic intracerebral hemorrhage but increased mortality and reduced favorable outcome in patients with UKO stroke compared with patients treated within the approved time window.

Paramedic Assessment of Older Adults After Falls, Including Community Care Referral Pathway: Cluster Randomized Trial.

STUDY OBJECTIVE: We aim to determine clinical and cost-effectiveness of a paramedic protocol for the care of older people who fall. METHODS: We undertook a cluster randomized trial in 3 UK ambulance services between March 2011 and June 2012. We included patients aged 65 years or older after an emergency call for a fall, attended by paramedics based at trial stations. Intervention paramedics could refer the patient to a community-based falls service instead of transporting the patient to the emergency department. Control paramedics provided care as usual. The primary outcome was subsequent emergency contacts or death. RESULTS: One hundred five paramedics based at 14 intervention stations attended 3,073 eligible patients; 110 paramedics based at 11 control stations attended 2,841 eligible patients. We analyzed primary outcomes for 2,391 intervention and 2,264 control patients. One third of patients made further emergency contacts or died within 1 month, and two thirds within 6 months, with no difference between groups. Subsequent 999 call rates within 6 months were lower in the intervention arm (0.0125 versus 0.0172; adjusted difference -0.0045; 95% confidence interval -0.0073 to -0.0017). Intervention paramedics referred 8% of patients (204/2,420) to falls services and left fewer patients at the scene without any ongoing care. Intervention patients reported higher satisfaction with interpersonal aspects of care. There were no other differences between groups. Mean intervention cost was $23 per patient, with no difference in overall resource use between groups at 1 or 6 months. CONCLUSION: A clinical protocol for paramedics reduced emergency ambulance calls for patients attended for a fall safely and at modest cost.

Assessment of platelet function in patients with stroke using multiple electrode platelet aggregometry: a prospective observational study.

BACKGROUND: There is a link between high on-treatment platelet reactivity (HPR) and adverse vascular events in stroke. This study aimed to compare multiple electrode platelet aggregometry (MEA), in healthy subjects and ischaemic stroke patients, and between patients naive to antiplatelet drugs (AP) and those on regular low dose AP. We also aimed to determine prevalence of HPR at baseline and at 3-5 days after loading doses of aspirin. METHODS: Patients with first ever ischaemic stroke were age and sex-matched to a healthy control group. Three venous blood samples were collected: on admission before any treatment given (baseline); at 24 h and 3-5 days after standard treatment. MEA was determined using a Mutliplate® analyser and agonists tested were arachidonic acid (ASPI), adenosine diphosphate (ADP) and collagen (COL). RESULTS: Seventy patients (mean age 73 years [SD 13]; 42 men, 28 women) were age and sex-matched to 72 healthy subjects. Thirty-three patients were on antiplatelet drugs (AP) prior to stroke onset and 37 were AP-naive. MEA results for all agonists were significantly increased in AP-naive patients compared to healthy subjects: ADP 98 ± 31 vs 81 ± 24, p < 0.005; ASPI 117 ± 31 vs 98 ± 27, p < 0.005; COL 100 ± 25 vs 82 ± 20, p < 0.005. For patients on long term AP, 33% (10/30) of patients were considered aspirin-resistant. At 3-5 days following loading doses of aspirin, only 11.1% were aspirin resistant based on an ASPI cut-off value of 40 AU*min. CONCLUSIONS: Many patients receiving low dose aspirin met the criteria of aspirin resistance but this was much lower at 3-5 days following loading doses of aspirin. Future studies are needed to establish the causes of HPR and potential benefits of individualizing AP treatment based on platelet function testing.

The changes in clot microstructure in patients with ischaemic stroke and the effects of therapeutic intervention: a prospective observational study.

BACKGROUND: Stroke is the second largest cause of death worldwide. Hypercoagulability is a key feature in ischaemic stroke due to the development of an abnormally dense clot structure but techniques assessing the mechanics and quality of clot microstructure have limited clinical use. We have previously validated a new haemorheological technique using three parameters to reflect clot microstructure (Fractal Dimension (d f )) ex-vivo, real-time clot formation time (T GP ) and blood clot strength (elasticity at the gel point (G'GP)). We aimed to evaluate these novel clotting biomarkers in ischaemic stroke and changes of clot structure following therapeutic intervention. METHODS: In a prospective cohort study clot microstructure was compared in ischaemic stroke patients and a control group of healthy volunteers. Further assessment took place at 2-4 hours and at 24 hours after therapeutic intervention in the stroke group to assess the effects of thrombolysis and anti-platelet therapy. RESULTS: 75 patients (mean age 72.8 years [SD 13.1]; 47 male, 28 female) with ischaemic stroke were recruited. Of the 75 patients, 32 were thrombolysed with t-PA and 43 were loaded with 300 mg aspirin. The following parameters were significantly different between patients with stroke and the 74 healthy subjects: d f (1.760 ± .053 versus 1.735 ± 0.048, p = 0.003), TGP (208 ± 67 versus 231 ± 75, p = 0.05), G'GP (0.056 ± 0.017 versus 0.045 ± 0.014, p < 0.0001) and fibrinogen (3.7 ± 0.8 versus 3.2 ± 0.5, p < 0.00001). There was a significant decrease in d f (p = 0.02), G'GP (p = 0.01) and fibrinogen (p = 0.01) following the administration of aspirin and for d f (p = 0.003) and fibrinogen (p < 0.001) following thrombolysis as compared to baseline values. CONCLUSION: Patients with ischaemic stroke have denser and stronger clot structure as detected by d f and G'GP. The effect of thrombolysis on clot microstructure (d f ) was more prominent than antiplatelet therapy. Further work is needed to assess the clinical and therapeutic implications of these novel biomarkers.

Clinical relevance of genetic polymorphism in CYP2C9 gene to pharmacodynamics and pharmacokinetics of phenytoin in epileptic patients: validatory pharmacogenomic approach to pharmacovigilance.

AIMS AND OBJECTIVES: Variations in drug metabolizing genes are known to have a clinical impact on AED therapy. We genotyped normal and epileptic patient cohorts of monoethnic population of Kashmir valley for CYP2C9 gene and allelic polymorphism and investigated the effect of CYP2C9*2 and *3 polymorphism on the Pharmacokinetic and therapeutic and/or adverse pharmacodynamic responses to Phenytoin in the idiopathic epilepsy patients. METHODS: PCR-RFLP methods were used for genotyping of 121 normal controls and 92 idiopathic epilepsy patients for CYP2C9*2 and *3 polymorphism, the results were validated by direct sequencing. Phenytoin pharmacokinetic (PK) analysis in idiopathic epilepsy patients was done using a validated EMIT assay technique. Pharmacodynamic analysis was done by evaluating clinical response to phenytoin therapy and ADR monitoring. RESULTS: The respective frequencies of CYP2C9 *1, *2, and *3 alleles were 64%, 6.6%, 29.3%, and 58%, 9.8%, 32.6% in controls and idiopathic epilepsy patients from Kashmir valley. PK analysis revealed that AUC0–4 was a better surrogate biomarker of CYP2C9 metabolizer status compared to C4 and C0 concentrations alone. A comparison of “phenytoin response categories” among CYP2C9 Wild and Heterozygous groups did not reveal any significant difference between the groups (p=0.3800). CONCLUSION: CYP2C9* 3 was the most frequent mutant allele found in healthy controls and idiopathic epilepsy patients of ethnic Kashmiri population. CYP2C9 genotype based phenytoin therapy is highly relevant in Kashmiri population due to a high incidence of genetic variations associated with therapeutic and adverse responses to phenytoin. Phenytoin AUC0–4 tends to correlate better with genetic polymorphism of CYP2C9.

Prospective evaluation of blood coagulability and effect of treatment in patients with stroke using rotational thromboelastometry.

BACKGROUND: Stroke is the second largest cause of death worldwide. Abnormalities in hemostasis play an important role in the pathophysiology of ischemic stroke (IS). These hemostatic defects can be detected using rotational thromboelastometry (ROTEM) as a global method of measuring coagulation. This study assessed the effects of IS on blood hypercoagulability using ROTEM method, before and subsequent to therapeutic interventions. METHODS: In a prospective observational cohort study, whole blood coagulation using ROTEM, along with full blood count and standard coagulation tests, were compared between patients with IS and an age-matched control group of healthy volunteers. Further assessment took place at 2-4 hours and at 24 hours in the stroke group after therapy to assess the effects of therapeutic intervention. RESULTS: Seventy-two patients with IS were age-matched to 71 healthy subjects. Clotting time (CT) INTEM (P = .01) and maximum clot firmness (MCF) INTEM (P = .02) were significantly different between stroke patients at baseline and healthy subjects, but this difference disappeared when controlled for by smoking status. There was no association between ROTEM parameters and time from stroke symptom onset or stroke severity as reflected in The National Institute of Health Stroke Scale score. Significant but small changes in the values of MCF-EXTEM, clot formation time (CFT) EXTEM, and alpha-EXTEM CT were observed after therapeutic intervention (thrombolysis or aspirin treatment). CONCLUSIONS: ROTEM testing does not seem to detect a hypercoagulable state in patients with IS. Nonetheless, some ROTEM parameters had a small change after antiplatelet therapy or thrombolysis.

An update on ATP synthase inhibitors: A unique target for drug development in M. tuberculosis.

ATP synthase is a key protein in the oxidative phosphorylation process, as it aids in the effective production of ATP (Adenosine triphosphate) in all life's of kingdoms. ATP synthases have distinctive properties that contribute to efficient ATP synthesis. The ATP synthase of mycobacterium is of special relevance since it has been identified as a target for potential anti-TB molecules, especially Bedaquiline (BDQ). Better knowledge of how mycobacterial ATP synthase functions and its peculiar characteristics will aid in our understanding of bacterial energy metabolism adaptations. Furthermore, identifying and understanding the important distinctions between human ATP synthase and bacterial ATP synthase may provide insight into the design and development of inhibitors that target specific ATP synthase. In recent years, many potential candidates targeting the ATP synthase of mycobacterium have been developed. In this review, we discuss the druggable targets of the Electron transport chain (ETC) and recently identified potent inhibitors (including clinical molecules) from 2015 to 2022 of diverse classes that target ATP synthase of M. tuberculosis.

Qualitative assessment of compost engendered from municipal solid waste and green waste by indexing method.

The present study aims at quantification of the quality of three varieties of composts made from municipal solid waste, green waste and combined waste by critically evaluating their physicochemical attributes, effect on soil fertility and metal pollution risk. Each waste type was treated with effective micro-organisms to compare the compost quality using Quality Control Indices. The effect of microbial consortia on the wastes was prominent resulting in decreased pH levels and increased electrical conductivity. C/N ratio ranged between 14-24 for waste composts without microbial treatment, and 8-11 for microbial treated wastes. The fertility parameter was observed to be more in microbial treated waste composts. Also, heavy metals concentration in waste compost without effective microbial treatment was higher than the types given EM. Based on the fertility and clean indices, the treated and untreated municipal solid waste and combined waste compost belonged to class RU-1 and class D, respectively. Moreover, compost prepared from treated and untreated green waste belonged to classes B and C respectively. In general, the prepared CW and GW composts have medium to high fertilizing potential and are fit for domestic as well as commercial use. However, MSW compost is not fit for agricultural purposes as it didn't improve soil fertility to a greater extent but can be used as a soil conditioner in limited quantity as it can cause metal toxicity. For this reason, proper segregation of inputs at the start of a composting process is necessary to improve its quality before being put to agricultural use as any unbalanced or unchecked content of mixed waste will affect the overall compost quality.Implications: Significance of the work: The research dealt with different combinations of segregated wastes to analyze the best fit solid waste compost. Experiments were conducted on the actual landfill site area to simulate the conditions for the process. The manuscript provides evidence and other facts advocating the use of composting for waste management and ultimately reducing pollution caused by landfilling. It ought to cause a multiplier effect if the same is to be followed in other parts of the world, and thus working our way toward getting the Smart city project to fruition. The results of the study exhibit the differences in physiochemical nature of various types of composts. A treatment of microbial consortium with restrictions enabled a conducive atmosphere in the colonies to thrive faster and initiate the process of decomposition. We observed that treated samples converted faster into compost as compared to non-treated samples. We also observed the effect of treatment on fertility parameters of prepared compost samples. In general, it was found that the organic carbon and C/N ratio declined while the total nitrogen and total potassium was observed to increase with very little to no change in phosphorous content, with the inoculation of beneficial micro-organisms throughout the composting course. A reduction in the heavy metal levels was observed in samples treated with active micro-organisms. The compost classification into A, B, C, and D classes represents the quality of compost and further use in agricultural land on commercial levels. The quality index values were determined highest for green waste compost (GWC). The municipal solid waste compost (MSWC) exhibited lowest index values. Therefore, based on the quality index values, the utilization of GWC will aid in reutilizing the green waste and in boosting soil fertility and reduce the waste quantity generation rates. It's also necessary to make compost making widespread among the farmers for a sustainable environment. The GWC has been considered as a sustainable option of waste management, being economically and ecologically viable.

Machine learning-enabled predictive modeling to precisely identify the antimicrobial peptides.

The ubiquitous antimicrobial peptides (AMPs), with a broad range of antimicrobial activities, represent a great promise for combating the multi-drug resistant infections. In this study, using a large and diverse set of AMPs (2638) and non-AMPs (3700), we have explored a variety of machine learning classifiers to build in silico models for AMP prediction, including Random Forest (RF), k-Nearest Neighbors (k-NN), Support Vector Machine (SVM), Decision Tree (DT), Naive Bayes (NB), Quadratic Discriminant Analysis (QDA), and ensemble learning. Among the various models generated, the RF classifier-based model top-performed in both the internal [Accuracy: 91.40%, Precision: 89.37%, Sensitivity: 90.05%, and Specificity: 92.36%] and external validations [Accuracy: 89.43%, Precision: 88.92%, Sensitivity: 85.21%, and Specificity: 92.43%]. In addition, the RF classifier-based model correctly predicted the known AMPs and non-AMPs; those kept aside as an additional external validation set. The performance assessment revealed three features viz. ChargeD2001, PAAC12 (pseudo amino acid composition), and polarity T13 that are likely to play vital roles in the antimicrobial activity of AMPs. The developed RF-based classification model may further be useful in the design and prediction of the novel potential AMPs.

Support and Assessment for Fall Emergency Referrals (SAFER 1) trial protocol. Computerised on-scene decision support for emergency ambulance staff to assess and plan care for older people who have fallen: evaluation of costs and benefits using a pragmatic cluster randomised trial.

BACKGROUND: Many emergency ambulance calls are for older people who have fallen. As half of them are left at home, a community-based response may often be more appropriate than hospital attendance. The SAFER 1 trial will assess the costs and benefits of a new healthcare technology--hand-held computers with computerised clinical decision support (CCDS) software--to help paramedics decide who needs hospital attendance, and who can be safely left at home with referral to community falls services. METHODS/DESIGN: Pragmatic cluster randomised trial with a qualitative component. We shall allocate 72 paramedics ('clusters') at random between receiving the intervention and a control group delivering care as usual, of whom we expect 60 to complete the trial.Patients are eligible if they are aged 65 or older, live in the study area but not in residential care, and are attended by a study paramedic following an emergency call for a fall. Seven to 10 days after the index fall we shall offer patients the opportunity to opt out of further follow up. Continuing participants will receive questionnaires after one and 6 months, and we shall monitor their routine clinical data for 6 months. We shall interview 20 of these patients in depth. We shall conduct focus groups or semi-structured interviews with paramedics and other stakeholders.The primary outcome is the interval to the first subsequent reported fall (or death). We shall analyse this and other measures of outcome, process and cost by 'intention to treat'. We shall analyse qualitative data thematically. DISCUSSION: Since the SAFER 1 trial received funding in August 2006, implementation has come to terms with ambulance service reorganisation and a new national electronic patient record in England. In response to these hurdles the research team has adapted the research design, including aspects of the intervention, to meet the needs of the ambulance services.In conclusion this complex emergency care trial will provide rigorous evidence on the clinical and cost effectiveness of CCDS for paramedics in the care of older people who have fallen. TRIAL REGISTRATION: ISRCTN10538608.

Emerging opportunities of exploiting mycobacterial electron transport chain pathway for drug-resistant tuberculosis drug discovery.

Introduction: Tuberculosis (TB) is a leading infectious disease worldwide whose chemotherapy is challenged by the continued rise of drug resistance. This epidemic urges the need to discover anti-TB drugs with novel modes of action.Areas covered: The mycobacterial electron transport chain (ETC) pathway represents a hub of anti-TB drug targets. Herein, the authors highlight the various targets within the mycobacterial ETC and highlight some of the promising ETC-targeted drugs and clinical candidates that have been discovered or repurposed. Furthermore, recent breakthroughs in the availability of X-ray and/or cryo-EM structures of some targets are discussed, and various opportunities of exploiting these structures for the discovery of new anti-TB drugs are emphasized.Expert opinion: The drug discovery efforts targeting the ETC pathway have led to the FDA approval of bedaquiline, a FOF1-ATP synthase inhibitor, and the discovery of Q203, a clinical candidate drug targeting the mycobacterial cytochrome bcc-aa3 supercomplex. Moreover, clofazimine, a proposed prodrug competing with menaquinone for its reduction by mycobacterial NADH dehydrogenase 2, has been repurposed for TB treatment. Recently available structures of the mycobacterial ATP synthase C9 rotary ring and the cytochrome bcc-aa3 supercomplex represent further opportunities for the structure-based drug design (SBDD) of the next-generation of inhibitors against Mycobacterium tuberculosis.

Denouement of Chemicals on Amyotrophic Lateral Sclerosis: Is Green Chemistry the Answer.

Medicinal Chemistry has played a critical role in evolving new products, resources and processes which inexorably correspond to our high standards of living. Unfortunately, this has also caused deterioration of human health and threats to the global environment, even deaths when highly exposed to certain chemicals, whether due to improper use, mishandling or disposal. There are chemicals, which apart from being carcinogens, endocrine disruptors or neurotoxins, are also responsible for climate change and ozone depletion. Certain chemicals are known to cause neurotoxicity and are having tendencies to damage the central and peripheral nervous system or brain by damaging neurons or cells which are responsible for transmitting and processing of signals. This has raised serious concerns for the use and handling of such chemicals and has given growth to a relatively new emerging field known as Green Chemistry that strives to achieve sustainability at the molecular level and has an ability to harness chemicals to meet environmental and economic goals. It has been reported in the literature that apart from family history in the aetiology of Amyotrophic lateral Sclerosis (ALS), also termed as "Lou Gehrig's disease", a neurological disorder, environmental factors, heavy metals, particularly selenium, lead, mercury, cadmium, formaldehyde, pesticides and certain herbicides are known to cause ALS. ALS, a progressive neurodegenerative disease affects the motor cortex, brain stem and spinal cord, causing muscular weakness, spasticity, and hyperreflexia. In this article we are aiming to discuss and summarize the various corroborations and findings supporting the undesirable role of chemical substance/herbicides/pesticides in ALS aetiology and its mitigation by adopting green chemistry.

Effect of environmental toxicants on neuronal functions.

In the last few years, neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD) have attracted attention due to their high prevalence worldwide. Environmental factors may be one of the biggest reasons for these diseases related to neuronal dysfunctions. Most of neuronal disorders are strongly associated with pre- and postnatal exposure to environmental toxins released from industries. Some of the neurotoxic metals such as lead, aluminum, mercury, manganese, cadmium, and arsenic as well as some pesticides and metal-based nanoparticles have been involved in AD and PD due to their ability to produce senile/amyloid plaques and NFTs which are the main feature of these neuronal dysfunctions. Exposure to solvents is also majorly responsible for neurodegenerative disorders. The present review highlights the impact of omnipresent heavy metals with some other neurotoxins on human health and how they give rise to neuronal dysfunctions which in turn causes socio-economic consequences due to increasing pollution worldwide. Graphical abstract.

In vitro bactericidal activity of 3-cinnamoyl-4-hydroxy-6-methyl-2-pyrone (CHP) against drug-susceptible, drug-resistant and drug-tolerant isolates of Mycobacterium tuberculosis.

OBJECTIVES: Tuberculosis (TB) poses a serious global threat to humans. New bactericidal agents that can shorten treatment duration and target drug resistance still remain a top priority in the discovery of anti-TB drugs. The objective of this study was to investigate the bactericidal potential of 3-cinnamoyl-4-hydroxy-6-methyl-2-pyrone (CHP) against drug-susceptible, drug-resistant clinical isolates and drug-tolerant Mycobacterium tuberculosis. METHODS: The minimum bactericidal concentration (MBC) was determined by colony-forming unit (CFU) enumeration. The kill curve analysis was done at different concentrations spanning over 16 days. Drug combination studies with antituberculosis drugs were done to investigate possible synergy. The potential against drug- resistant isolates of M. tuberculosis was done by broth dilution assay. CFU enumeration was done to determine its activity against nutrient-starved drug tolerants, and its feasibility for oral administration was tested by serum inhibitory titre. RESULTS: CHP displayed bactericidal activity with an MBC of 4 µg/mL against M. tuberculosis H37Rv. The kill curve analysis exhibited a biphasic pattern of killing. CHP showed synergy with rifampicin, isoniazid and amikacin but was indifferent towards ethambutol and levofloxacin. CHP retained its full activity against drug-susceptible, monoresistant and multidrug-resistant (MDR) clinical isolates. CHP showed very strong bactericidal activity against nondividing, drug-tolerant M. tuberculosis that on comparison was highly superior to rifampicin. Furthermore, CHP significantly improved the bactericidal activity of rifampicin and isoniazid in a combination study. The serum inhibitory titre in mice indicated its high oral bioavailability. CONCLUSION: Our results show strong bactericidal potential of CHP against M. tuberculosis that warrant its immediate mechanistic, pharmacokinetic and pharmacodynamic studies.