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Tuberculosis (TB) continues to be a major cause of death worldwide that can be effectively treated with timely diagnosis and treatment. With the advent of nuclear imaging techniques like 18Fluorine Fluoro-2-Deoxy-D-Glucose Positron Emission Tomography (18F-FDG) PET/CT, the diagnosis of tuberculosis, particularly its extrapulmonary forms, has received great impetus in cases where microbiological confirmation cannot be achieved. Although detection of mycobacteria either by staining, culture or nucleic acid amplification techniques still form the gold standard of diagnosis, newer diagnostic techniques are always welcome in the field which can expedite clinical management. Use of radiolabeled antibiotics is one such evolving sphere which needs further research. Moving ahead from radiolabeled leukocytes, antibiotics are being increasingly focused upon to act as a vehicle to locate infectious lesions. Antibiotics like ciprofloxacin have been labeled with diagnostic radionuclides such as Technetium-99m (Tc-99m) and used to image many infectious diseases with encouraging results in TB. However, the nonspecific attributes of ciprofloxacin have hindered its growth to assist the diagnosis of TB. A novel approach would be to utilize ethambutol, a specific antitubercular agent, which has been found to be safe and effective in the diagnosis of TB in the available published studies. Ethambutol is known to be taken up specifically by tubercular lesions. This forms the basis of using Tc-99m labelled ethambutol for imaging TB lesions. An added advantage would be its ability to differentiate tubercular from malignant and fungal lung lesions that are the usual differentials in patients suspected of having TB. Most of the studies involving ethambutol have been done in skeletal TB and its validation in other forms of TB is still awaited. Recently the role of PET-CT has also been explored in human studies using 11C Rifampicin to study the antibiotic uptake in tubercular lesions. This review summarizes the available evidence regarding diagnosis of TB by radiolabeled antibiotic imaging to emphasize the need for accelerated research in the fight against TB.

We present here an improved procedure for the preparation of the promising antitubercular drug SQ109 that is currently in phase Ib/III of clinical trials against Mycobacterium tuberculosis. We investigated and tested the literature synthetic procedure that enables the development of structure–activity relationships and report the observed inconsistencies as well as presenting improvements or novelties for the more efficient preparation of SQ109. Most significantly we applied a novel reduction step of the aminoamide precursor using Me3SiCl­/LiAlH4 under mild conditions. These findings are important for research groups investigating the efficacy of this drug and analogues in academia and industry.

An unprecedented cross-coupling reaction of alkyl carbagermatranes with bromofluoroolefins to deliver dialkyl-substituted monofluoroalkenes was achieved. This cross-coupling reaction was performed under base/additive-free conditions with excellent functional group tolerance, therefore offering an opportunity for challenging dialkyl-substituted monofluoroalkenes. The preparation of bioactive agent analogues including an antitubercular agent mimic and a COX-2 inhibitor analogue and the late-stage fluoroalkenylation of drug-molecule derivatives proved the utility of this strategy.

Little is known about the relationship between the COVID-19 and tuberculosis (TB). The aim of this study is to describe a group of patients who died with TB (active disease or sequelae) and COVID-19 in two cohorts. Data from 49 consecutive cases in 8 countries (cohort A) and 20 hospitalised patients with TB and COVID-19 (cohort B) were analysed and patients who died were described. Demographic and clinical variables were retrospectively collected, including co-morbidities and risk factors for TB and COVID-19 mortality. Overall, 8 out of 69 (11.6%) patients died, 7 from cohort A (14.3%) and one from cohort B (5%). Out of 69 patients 43 were migrants, 26/49 (53.1%) in cohort A and 17/20 (85.0%) in cohort B. Migrants: (1) were younger than natives; in cohort A the median (IQR) age was 40 (27–49) VS. 66 (46–70) years, whereas in cohort B 37 (27–46) VS. 48 (47–60) years; (2) had a lower mortality rate than natives (1/43, 2.3% versus 7/26, 26.9%; p-value: 0.002); (3) had fewer co-morbidities than natives (23/43, 53.5% versus 5/26–19.2%) natives; p-value: 0.005). The study findings show that: (1) mortality is likely to occur in elderly patients with co-morbidities; (2) TB might not be a major determinant of mortality and (3) migrants had lower mortality, probably because of their younger age and lower number of co-morbidities. However, in settings where advanced forms of TB frequently occur and are caused by drug-resistant strains of M. tuberculosis, higher mortality rates can be expected in young individuals.

Background: A series of 1-(2-(2-amino-5-carbamoyl-6-(1-(substitutedphenyl) prop-1-enyl) pyrimidin-4-yloxy)acetyl) semicarbazide (4a-i) derivatives was synthesized from substituted aromatic aldehydes, ethyl cyanoacetate and guanidine hydrochloride and characterized by analytical and spectral data, FTIR, 1H-NMR and Mass spectroscopy data. Methods: The antiTB action of the synthesized compounds was screened in comparison with the standard drug Rifampicin using MABA assay method. The SAR of substituted aromatic aldehydes with modification at ortho, meta and para positions with electron withdrawing group. Results: The compounds 1-(2-(2-amino-5- carbamoyl-6-(1-(2-fluorophenyl) prop-1-enyl) pyrimidin-4- yloxy) acetyl) semicarbazide and 1-(2-(2-amino- 5-carbamoyl-6-(1-(3-chlorophenyl) prop-1-enyl) pyrimidin-4-yloxy) acetyl) semicarbazide showed equal MIC values against Mycobacterium tuberculosis H37Ra with the value of 3.90μg/ml. Conclusion: The SAR study revealed that the antiTB activity of the synthesized compounds were affected by lipophilicity of the substituent.

Antitubercular agent levesquamide is a new polyketide-nonribosomal peptide (PK-NRP) hybrid marine natural product isolated from Streptomyces sp. RKND-216. The structure contains a rare isothiazolinone moiety which has only been reported in collismycin SN. Structure elucidation by NMR spectroscopy was a significant challenge due to a deficiency of protons in this aromatic moiety. Therefore, the genome of Streptomyces sp. RKND-216 was sequenced to identify the levesquamide biosynthetic gene cluster (BGC). Analysis of the BGC provided structural insights and guided stable-isotope labeling experiments, which led to the assignment of the fused pyridine-isothiazolinone moiety. The BGC and the labeling experiments provide further insights into the biosynthetic origin of isothiazolinones. Levesquamide exhibited antimicrobial activity in the microplate alamarBlue assay (MABA) and low oxygen recovery assay (LORA) against Mycobacterium tuberculosis H37Rv with minimum inhibitory concentration (MIC) values of 9.65 and 22.28 μM, respectively. Similar activity was exhibited against rifampicin- and isoniazid-resistant M. tuberculosis strains with MIC values of 9.46 and 9.90 μM, respectively. This result suggests levesquamide has a different mode of action against M. tuberculosis compared to the two first-line antitubercular drugs rifampicin and isoniazid. Furthermore, levesquamide shows no cytotoxicity against the Vero cell line, suggesting it may have a useful therapeutic window.

Tuberculosis represents a major global health problem for which improved approaches are needed to shorten the course of treatment and to combat the emergence of resistant strains. The development of effective and safe nanobead-based interventions can be particularly relevant for increasing the concentrations of antitubercular agents within the infected site and reducing the concentrations in the general circulation, thereby avoiding off-target toxic effects. In this work, rifampicin, a first-line antitubercular agent, was encapsulated into biocompatible and biodegradable polyester-based nanoparticles. In a well-established BALB/c mouse model of pulmonary tuberculosis, the nanoparticles provided improved pharmacokinetics and pharmacodynamics. The nanoparticles were well tolerated and much more efficient than an equivalent amount of free rifampicin.

In Japan, tuberculosis has been recognized as one of the major infections requiring urgent measures because of its high morbidity rate even now especially in elderly people suffering from tuberculosis during the past epidemic and its reactivation. Hence, many Japanese clinicians have made efforts to suppress the onset of tuberculosis and treat it effectively. The objectives of this study are to (1) identify covariate(s) that may explain the variation of rifampicin, which is the key antitubercular agent, under the steady-state by evaluating its population pharmacokinetics and (2) to propose an appropriate dosing method of rifampicin to Japanese patients. For this purpose, serum concentration–time data were obtained from 138 patients receiving rifampicin (300–450 mg) and isoniazid (300–400 mg) every day over 14 days, and analyzed using nonlinear mixed effects model. Thereby, population pharmacokinetic parameters were estimated followed by elucidating relations between the parameters and statistical factors. The analysis adopted one-compartment model including Lag-time by assuming that the absorption process is 0+1st order. The analyses demonstrate that meal affected the bioavailability, primary absorption rate constant, and zero order absorption time in the constructed model. A body weight calculated from the power model was selected as the covariate by the Stepwise Covariate Model method and found to highly affect the clearance in the range from −31.6% to 47.4%. We conclude that the dose in Japanese tuberculous patients can be well estimated by the power model formula and should be taken into consideration when rifampicin is administered.

We initiated a program to synthesize thiazolidinone derivatives as antitubercular agent by preparing hybrid molecules having the similar features of reported potent antitubercular agents. We desire to state the advancement and execution of a methodology allowing for the synthesis of some new (Z)-5-(substituted benzylidene)-2-((substituted phenyl) amino)thiazol-4(5H)-one analogues with antitubercular activity. A highly efficient protocol was developed for the synthesis with excellent yields as well as evaluated in vitro for their antimycobacterial activity against Mycobacterium tuberculosis MTB H37Ra and M. bovis BCG strains. Among these synthesized compounds 6a, 6c, 6e, 6f and 6i showed marginal antitubercular activity in the series along with no significant cytotoxicity against the MCF-7 and A549 human cancer cell lines.

Curcumin is an active component of turmeric that has poor solubility, stability and bioavailability. The monocarbonyl curcumin analogues were modified from curcumin to achieve more stable and active compounds as compared to curcumin. Therefore, we have designed and synthesized a library of 18 compounds of α,α’-bis(1H-1,2,3-triazol-5-ylmethylene) ketones (8a–o) and evaluated them for their in vitro antitubercular and antioxidant activities against their respective strains. Results of biological activities reveal that some of the compounds from the series showed good antitubercular as well as antioxidant activities. The compound 8l was found as the most active antitubercular agent with MIC value 3.125 µg/mL, against Mtb H37Rv. Moreover, the compounds, 8c, 8d, 8e and 8g, also showed potent antitubercular activity. The compounds 8e and 8m displayed potent antioxidant activities with IC50 values 15.60 and 15.49 µg/mL, respectively. In support of the bioactivities, in silico ADME properties’ prediction has also been carried out in this study.

A series of 1-(1-benzyl-2-methyl-5-((1-phenyl-1H-1,2,3-triazol-4-yl)methoxy)-1H-indol-3-yl)ethanone and ethyl 1-benzyl-2-methyl-5-((1-phenyl-1H-1,2,3-triazol-4-yl)methoxy)-1H-indole-3-carboxylate derivatives were designed based on bioisosteric replacement of previously reported antitubercular agent (IND-07). Twenty ligands were successfully synthesized and some of them were found to have good in vitro activity (MIC 10 μM) against the H

A series of meta-amido bromophenol derivatives were designed and synthesized. The compounds were found to potently inhibit the growth of Mycobacterium tuberculosis H37Ra. They also exhibited moderate inhibitory activity against Mycobacterium tuberculosis H37Rv and multidrug-resistant strains. The compounds did not show inhibitory activity against normal Gram-positive and Gram-negative bacteria. Moderate cytotoxicities and good metabolic stability were observed for the selected compounds. The results demonstrated meta-amido bromophenols as a new class of antitubercular agents with good potentials.

Tuberculosis (TB) is a global health disaster and is a wide-reaching hitch. The improper use of antibiotics in chemotherapy of TB patients led to the current problem of tuberculosis therapy which gives rise to Multi-Drug Resistant (MDR) strains. Nitrogen heterocycles including azole compounds are an important class of therapeutic agent with electron-rich property. Azole-based derivatives easily bind with the enzymes and receptors in organisms through noncovalent interactions, thereby possessing various applications in medicinal chemistry. Research on azoles derivatives have been expansively carried out and have become one of the extremely active area in recent years and the progress is quite rapid. A genuine attempt to review chemistry of azoles and to describe various azole-based compounds synthesized in the last two decades having promising antitubercular potential is described in the present article. It is hopeful that azole compounds may continue to serve as an important direction for the exploitation of azole-based antitubercular drugs with better curative effect, lower toxicity, less side effects, especially fewer resistances and so on.

The diagnosis of tuberculosis (TB) continues to pose substantial public health problems. The quest for diagnostic biomarkers for TB is therefore primordial. This study aimed to evaluate the diagnostic and anti-TB treatment monitoring potentials of some selected miRNAs. Quantitative real time polymerase chain reaction and Receiver operating characteristics were used to estimate the ability of miRNAs to discriminate between healthy controls (HEC), latent (LTB) and active TB (ATB). The study showed that: hsa-miR-29a-3p, hsa-miR-155-5p and hsa-miR-361-5p were significantly upregulated in ATB compared to HEC while hsa-miR-29a-3p, and hsa-miR-361-5p were also significantly up-regulated in ATB compared to LTB (all P ≤ 0.05). MiR-29a-3p showed a good (81.37%) distinguishing performance in discriminating ATB from HEC and a good (84.35%) diagnostic performance in discriminating ATB from LTB. The performance of miR-29a-3p present in the blood in discriminating active TB from latent TB and healthy controls indicates it may be a useful biomarker for diagnosis of TB. Because this miRNA is found in blood (plasma) which is easy to collect compared to sputum it could be used in pediatric and extra-pulmonary TB cases.

The aim of this work was to be combine two pharmocophoric nuclei viz, triazole and chalcone and evaluate their antitubercular activity. Propargylated vanillin was condensed with differently substituted acetophenones to produce various chalcones (3a-c). Propargyl chalcones were then made to react with benzyl azides (2a-d) using the technique of Click chemistry and this reaction yielded triazole-chalcone hybrids (4a-l) in good yields, ranged from 34 to 93%. These hybrids were evaluated for their antitubercular activity, from the results it was found that triazole and chalcone on combination exhibited enhanced bioactivity thereby supported the theory of synergistic effect. The conjugate 4a and 4f were found to be most potent with MIC of 1.6 µg/ml. Molecular docking studies of bioactive compounds were in good congruence with in-vitro studies.

International audience; A novel coumarin-based molecule, designed as a fluorescent surrogate of a thiacetazone-derived antitubercular agent, was quickly and easily synthesized from readily available starting materials. This small molecule, coined Coum-TAC, exhibited a combination of appropriate physicochemical and biological properties, including resistance toward hydrolysis and excellent antitubercular efficiency similar to that of well-known thiacetazone derivatives, as well as efficient covalent labeling of HadA, a relevant therapeutic target to combat Mycobacterium tuberculosis. More remarkably, Coum-TAC was successfully implemented as an imaging probe that is capable of labeling Mycobacterium tuberculosis in a selective manner, with an enrichment at the level of the poles, thus giving for the first time relevant insights about the polar localization of HadA in the mycobacteria.

More than two decades have elapsed since the publication of the first genome sequence of Mycobacterium tuberculosis (Mtb) which, shortly thereafter, enabled methods to determine gene essentiality in the pathogen. Despite this, target-based approaches have not yielded drugs that have progressed to clinical testing. Whole-cell screening followed by elucidation of mechanism of action has to date been the most fruitful approach to progressing inhibitors into the tuberculosis drug discovery pipeline although target-based approaches are gaining momentum. This review discusses scaffolds that have been identified over the last decade from screens of small molecule libraries against Mtb or defined targets where mechanism of action investigation has defined target-hit couples and structure-activity relationship studies have described the pharmacophore.

Objectives A growing amount of evidence suggests that the rifampicin dosing currently recommended for tuberculosis treatment could be associated with inadequate exposure and unfavourable outcomes. We aimed to compare clinical and microbiological efficacy and safety outcomes of standard and higher rifampicin dosing. Methods Data sources were MEDLINE, Google Scholar and the Cochrane Library. This was a systematic review and meta-analysis that included experimental or observational studies comparing 8-week sputum culture conversion, treatment failure, or safety outcomes in naive patients with pulmonary tuberculosis treated with standard (10 mg/kg) or higher doses of rifampicin. Results Of a total of 9683 citations screened, eight randomized controlled trials were included, accounting for 1897 subjects; the risk of bias was low in three studies, high in two and intermediate in three. At week 8 a higher proportion of patients in the high-dose group obtained a sputum culture conversion than those in the standard dose group (83.7% versus 80.6%, RR 1.06; 95%CI 1.01–1.12, p 0.028); this result was confirmed in the sub-analysis including patients treated with a rifampicin dose of ≥20 mg/kg, but not in those treated with 11–19 mg/kg. Events of treatment failure at end of treatment showed no significant difference between the two groups (RR 0.84; 95%CI 0.59–1.21, p 0.362). In the analysis evaluating safety outcome, the difference in the occurrence of a grade 3 or 4 liver toxicity or adverse drug reactions leading to discontinuation was not significant at the statistical analysis among the groups (7.2% versus 5.4%, RR 1.19; 95%CI 0.81–1.73, p 0.370, and 1.5% versus 0.6%, RR 2.31; 95%CI 0.65–8.21, p 0.195, respectively). No statistical heterogeneity among studies was observed for each outcome. Conclusions High doses of rifampicin were associated with an increased rate of sputum culture conversion at 8 weeks of treatment, particularly in patients receiving ≥20 mg/kg.

Background Tuberculosis (TB) caused by Mycobacterium tuberculosis is one of the main killers of people all over the world. The major hurdles with existing therapy are the lengthy regimen and appearance of multi drug resistant (MDR) and extensively drug resistant (XDR) strains of M.tuberculosis. Aims The present work was aimed to synthesize and determine antitubercular and antimicrobial potential of some novel 3-chloro-4-aryl-1-[4-(5-pyrazin-2-yl[1,3,4]oxadiazole-2-ylmethoxy)-phenyl]-azetidin-2-one derivatives 7(a-h) from pyrazinoic acid as precursor, which is a well-established antitubercular agent. Here we report the synthesis of a new class of heterocyclic molecules in which pyrazine, 1, 3, 4-oxadiazole and azetidinone moieties were present in one frame work. Methods Pyrazinoic acid (1) was esterified first (2) followed by amination to produce hydrazide (3) which was refluxed with POCl3 to obtain 2-chloromethyl-5pyrazino-1, 3, 4-oxadiazole (4). This was then further reacted with 4-amino phenol to obtain 4-[5-pyrazino-1, 3, 4-oxadiazol-2-yl-methoxy]-phenyl amine (5) which on condensation with various aromatic aldehydes afforded a series Schiff’s bases 6(a-h). Dehydrative annulations of 6(a-h) in the presence of chloroacetyl chloride and triethylamine yielded 3-chloro-4-aryl-1-[4-(5-pyrazin-2-yl-[1, 3, 4]oxadiazole-2-ylmethoxy)-phenyl]-azetidin-2-one derivatives 7(a-h). Antibacterial, antifungal and antitubercular potential of all the synthesized compounds were assessed. Docking study was performed using the software VLife Engine tools of Vlifemds 4.6 on the protein lumazine synthase of M. tuberculosis (PDB entry code 2C92). Results The present studies demonstrated that synthesized oxadiazole derivatives have good antimicrobial activity against the various microorganisms. Among the synthesized derivative, 7b and 7g were found to be prominent compounds which have potential antibacterial, antifungal and antitubercular activity (with MIC 3.12 µg/ml and high dock score ranging from −59.0 to −54.0) against Mycobacterium tuberculosis. Conclusions Derivatives 7b and 7g would be effective lead candidates for tuberculosis therapy.

– OBJECTIVE: We propose a revised flow chart of spinal infection multidisciplinary management project (SIMP) aimed to standardize the diagnostic process and management of spinal tuberculosis (TB). MATERIALS AND METHODS: We reviewed data from all TB cases with osteoarticular involvement treated at a large tertiary teaching hospital in Bologna, Northern Italy, from January 2013 to December 2017. We cross-linked notified osteoarticular TB cases with SIMP database and we analysed clinical, diagnostic, and treatment data of all cases managed by SIMP. RESULTS: Osteoarticular TB accounted for the 7.8% (n=40) of all TB cases notified between 2013 and 2017 (N=513). Among the identified cases, 52% (n=21/40) had spine involvement: all were enrolled and evaluated by SIMP multidisciplinary group. Females accounted for 57% (12/21) of patients, the median age was 52 years (range 24-82). In the 67% (n=14/21) of cases, the major clinical symptom of spinal TB was back pain reported for a median of 4.5 months (range 1-12 months) before hospital admission. The interferon gamma release assay was positive in 75% (n=16/21) of patients. All patients performed MRI with gadolinium, which indicated spondylodiscitis in 90%. 18F-FDG-PET/CT revealed average maximum standardized uptake value (SUV max) of 12.54 (range 5.3-22) in 17/19 (89.5%). Bacteriological confirmation of TB was obtained in 86% of cases (n=18/21). One-third of patients (7/21) underwent surgery and 95% successfully completed the anti-TB treatment. CONCLUSIONS: Our data reveal that a multidisciplinary approach to spine tuberculosis facilitates early and accurate diagnosis and can improve medical and surgical management of this disease.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) pandemic has attracted interest because of its global rapid spread, clinical severity, high mortality rate, and capacity to overwhelm healthcare systems [1, 2]. SARS-CoV-2 transmission occurs mainly through droplets, although surface contamination contributes and debate continues on aerosol transmission [3–5].

Introduction: Rifabutin (RFB) is a lipophilic, semi-synthetic antibiotic given for the treatment of atypical mycobacterial infections along with drug susceptible tuberculosis infections. The major challenges in its usage include low oral bioavailability (~20%) mainly due to its low solubility and extensive first pass metabolism. Aim: The present study aims to explore the pharmacokinetics, biodistribution and toxicity of nanocarrier of RFB. Materials and Methods: An experimental animal study was carried out in Institute for Industrial Research and Toxicology, Ghaziabad, Uttar Pradesh, India. RFB nanocarriers were formulated by using solvent diffusion evaporation method with minor modifications and characterised for its physicochemical properties by using various techniques like Field Emission Scanning Electron Microscopy (FESEM), Dynamic Light Scattering (DLS) method, High-Performance Liquid Chromatography (HPLC), X-ray Diffractometry (XRD), in-vitro release study etc. Further nanocarriers were also studied for in-vivo analysis using pharmacokinetics, biodistribution and toxicity studies. GraphPad Prism Software (Version 5.02) was used for the statistical analysis. Results: Nanocarriers of RFB were developed and evaluated for its safety and efficacy. The results of evaluation of nanocarrier for physical and chemical attributes revealed that its particle size obtained was 305-325 nm with low Poly Dispersity Index (PDI) of 0.26-0.36 and the high drug encapsulation efficiency (62.45-70.15%). The nanocarrier formulation showed a sustained release pattern in Simulated Intestinal Fluid (SIF) upto 48 hours and in Physiological Buffer System (PBS) upto 7 days. The in-vivo study showed that the nano-lipoidal drug has significant higher Tmax and Cmax plasma value with higher t1/2(h) values in comparison to plain drug. Moreover, the slow elimination rate (Kel) resulted in significant (p

Isoniazid, the choice antitubercular agent, has only been employed against Mycobacterium tuberculosis. This study evaluated if the enzyme-mimetic activities of magnetic nanoparticles could accelerate the activation process of isoniazid against mycobacterial and, more importantly, non-mycobacterial microorganisms. First, magnetic nanoparticles were synthesized and coated by lipoamino acid; then, isoniazid was conjugated to synthesized nanoparticles. Antibacterial activities of nanoconjugated isoniazid were evaluated against Mycobacterium tuberculosis and four Gram-positive and Gram-negative nonmycobacterial strains through a microdilution broth process. Results showed that the required amount of isoniazid against Mycobacterium tuberculosis would decrease to 44.8% and 16.7% in conjugation with naked and surface-modified magnetic nanoparticles, respectively. Also, 32 μg/mL and 38 μg/mL of isoniazid in conjugation with naked and surface-modified nanoparticles, respectively, could prevent the growth of Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. Hence, the vicinity of magnetic nanoparticles with isoniazid could declare promising aspects of isoniazid antibacterial capabilities.

The present study describes L-hydroxy proline catalyzed unpredicted formation of 4,5-dihydro-1H-pyrazolo[3,4-b]pyridines instead of expected 4,7-dihydro-1H-pyrazolo[3,4-b]pyridines in aqueous ethan...

Background Human Immunodeficiency Virus (HIV) infection is a risk factor for tuberculosis (TB). Antiretroviral therapy (ART) changed HIV clinical management but it is still unclear how pre-existing HIV/Mycobacterium tuberculosis (Mtb)-specific CD4+ and CD8+ T-cells are restored. Aim to evaluate the impact of ART and TB therapies on the functional and phenotypic profile of Mtb-specific antigen-response of CD4+ and CD8+ T-cells in prospectively enrolled HIV-TB co-infected patients. Methods ART-naive HIV-infected patients, with or without active TB or latent TB infection (LTBI), were enrolled before and after starting ART and TB therapies. Peripheral blood mononuclear cells (PBMC) were stimulated overnight with Mtb and HIV antigens (GAG). Cytokine expression and phenotype profile were evaluated by flow cytometry. Cytomegalovirus (CMV) and staphylococcal enterotoxin B (SEB) were also used. Results The median of absolute number of CD4+ T-cells increased after ART and TB therapies in all groups analyzed, while the median of absolute number of CD8+ T-cells decreases in HIV and HIV-LTBI groups. Treatments significantly increased the frequency of Mtb-specific CD4+ T-cells in the HIV-LTBI (p = 0.015) with a rise of the central memory compartment. The magnitude of the CD4+ T-cell response to HIV-GAG significantly increased in active TB (p = 0.03), whereas the magnitude of CMV-specific CD4+ T-cell response decreased in all the groups. Similarly, the treatments increased the number of Mtb-specific CD8+ responders in both HIV-LTBI and HIV-TB groups, whereas the phenotype distribution was dependent on the antigens used and on the stage of infection/disease. Conclusions After therapies the median of absolute number and the proportion of CD4+ T-cells increased in all groups whereas the median of absolute count and proportion of CD8+ T-cells decreased in the HIV and HIV-LTBI subjects. Interestingly, an increased frequency of CD4+ T-cell response to RD1 proteins in HIV-LTBI subjects was found. These results contribute to a better understanding of the effect of ART and TB therapies on the modulation of Mtb-specific CD4+ and CD8+ T-cells subsets.

Tuberculosis remains a global concern. There is an urgent need of newer antitubercular drugs due to the development of resistant forms of Mycobacterium tuberculosis (Mtb). Inosine 5'-monophosphate dehydrogenase (IMPDH), guaB2, of Mtb, required for guanine nucleotide biosynthesis, is an attractive target for drug development. In this study, we screened a focused library of 73 drug-like molecules with desirable calculated/predicted physicochemical properties, for growth inhibitory activity against drug-sensitive MtbH37Rv. The eight hits and mycophenolic acid, a prototype IMPDH inhibitor, were further evaluated for activity on purified Mtb-GuaB2 enzyme, target selectivity using a conditional knockdown mutant of guaB2 in Mtb, followed by cross-resistance to IMPDH inhibitor-resistant SRMV2.6 strain of Mtb, and activity on human IMPDH2 isoform. One of the hits, 13, a 5-amidophthalide derivative, has shown growth inhibitory potential and target specificity against the Mtb-GuaB2 enzyme. The hit, 13, is a promising molecule with potential for further development as an antitubercular agent.

Recent tuberculosis (TB) drug discovery programme involve continuous pursuit for new chemical entity (NCE) which can be not only effective against both susceptible and resistant strains of Mycobacterium tuberculosis (Mtb) but also safe and faster acting with the target, thereby shortening the prolonged TB treatments. We have identified a potential nitrofuranyl methyl piperazine derivative, IIIM-MCD-211 as new antitubercular agent with minimum inhibitory concentration (MIC) value of 0.0072 μM against H37Rv strain. Objective of the present study is to investigate physicochemical, pharmacokinetic, efficacy and toxicity profile using in-silico, in-vitro and in-vivo model in comprehensive manner to assess the likelihood of developing IIIM-MCD-211 as a clinical candidate. Results of computational prediction reveal that compound does not violate Lipinski's, Veber's and Jorgensen's rule linked with drug like properties and oral bioavailability. Experimentally, IIIM-MCD-211 exhibits excellent lipophilicity that is optimal for oral administration. IIIM-MCD-211 displays evidence of P-glycoprotein (P-gp) induction but no inhibition ability in rhodamine cell exclusion assay. IIIM-MCD-211 shows high permeability and plasma protein binding based on parallel artificial membrane permeability assay (PAMPA) and rapid equilibrium dialysis (RED) assay model, respectively. IIIM-MCD-211 has adequate metabolic stability in rat liver microsomes (RLM) and favourable pharmacokinetics with admirable correlation during dose escalation study in Swiss mice. IIIM-MCD-211 has capability to appear into highly perfusable tissues. IIIM-MCD-211 is able to actively prevent progression of TB infection in chronic infection mice model. IIIM-MCD-211 shows no substantial cytotoxicity in HepG2 cell line. In acute toxicity study, significant increase of total white blood cell (WBC) count in treatment group as compared to control group is observed. Overall, amenable preclinical data make IIIM-MCD-211 ideal candidate for further development of oral anti-TB agent.

A series of novel quinazolin-4(3H)-one derivatives (4a-4j) were synthesized and were screened for their in vitro antibacterial activity against Gram-positive bacterial strains (Bacillus subtilis, Staphylococcus aureus, and Streptococcus pyogenes), and Gram-negative bacterial strains (Escherichia coli, Klebsiella pneumonia, S. typhimurium) and antifungal against Aspergillus niger, Candida albicans, Aspergillus flavus (Fungi). The compound 4c has been identified as potent antimicrobial agent. All the synthesized compounds were also studied for their In vitro antitubercular activity against MTB H37Rv. Compounds 4c and 4 g were identified as potent antitubercular agent with MIC value 0.78 μM and 1.56 μM. Additionally, data obtained during molecular docking studies are very encouraging with respect to potential utilization of these compounds to help overcome microbe resistance to pharmaceutical drugs, as clearly noted in this manuscript.