Drugs Isoniazid Research Articles

Green synthesis and in-vitro screening of 3-((4-(arylideneamino)phenyl) imino)indolin-2-one derivatives antimycobacterial agents

In this research article, we attempted to synthesize some new isatin derivatives, 3-((4-(arylideneamino)phenyl)imino)indolin-2-ones (2a-2g) by Schiff\'s base reaction under microwave technique. The structural characterizations of synthesized compounds were done by using different analytical techniques such as IR, 1HNMR, mass spectrometry, and elemental analysis. We aim to develop new compounds with improved antimycobacterial activities. These title compounds were screened for their antimycobacterial activity against the Mycobacterium tuberculosis H37Rv strain by using the microplate Alamar blue dye assay (MABA) method. All title compounds showed significant antimycobacterial activity. Compound 2g was found most potent compound with a MIC value of 6.25 µg/mL among all tested compounds when compared with standard drugs streptomycin (6.25µg/mL) and isoniazid (6.25 µg/mL).

Discovery of 1,2,3-triazole incorporated indole-piperazines as potent antitubercular agents: Design, Synthesis, In vitro biological evaluation, molecular docking and ADME studies

In this report, a library consisting of three sets of indole-piperazine derivatives was designed through the molecular hybridization approach. In total, fifty new hybrid compounds (T1-T50) were synthesized and screened for antitubercular activity against Mycobacterium tuberculosis H37Rv strain (ATCC-27294). Five (T36, T43, T44, T48 and T49) among fifty compounds exhibited significant inhibitory potency with the MIC of 1.6 µg/mL, which is twofold more potent than the standard first-line TB drug Pyrazinamide and equipotent with Isoniazid. N-1,2,3-triazolyl indole-piperazine derivatives displayed improved inhibition activity as compared to the simple and N-benzyl indole-piperazine derivatives. In addition, the observed activity profile of indole-piperazines was similar to standard anti-TB drugs (isoniazid and pyrazinamide) against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa strains, demonstrating the compounds’ selectivity towards the Mycobacterium tuberculosis H37Rv strain. All the active anti-TB compounds are proved to be non-toxic (with IC50 > 300 μg/mL) as verified through the toxicity evaluation against VERO cell lines. Additionally, molecular docking studies against two target enzymes (Inh A and CYP121) were performed to validate the activity profile of indole-piperazine derivatives. Further, in silico-ADME prediction and pharmacokinetic parameters indicated that these compounds have good oral bioavailability.

Unravelling performance of honeycomb structures as drug delivery systems for the isoniazid drug using DFT-D3 correction dispersion and molecular dynamic simulations.

In this study, the potential of aluminum nitride (h-AlN), boron nitride (h-BN) and silicon carbide (h-SiC) nanosheets as the drug delivery systems (DDS) of isoniazid (INH) was scrutinized through density functional theory (DFT) and molecular dynamic (MD) simulations. We performed DFT periodic calculations on the geometry and electronic features of nanosheets adsorbed with INH by the DFT functional (DZP/GGA-PBE) employed in the SIESTA code. In the energetically favorable model, an oxygen atom of the C-O group of the INH molecule interacts with a Si atom of the h-SiC at 2.077 Å with an interaction energy of -1.361 eV. Charge transfer (CT) calculation by employing the Mulliken, Hirshfeld and Voronoi approaches reveals that the monolayers and drug molecules act as donors and acceptors, respectively. The density of states (DOS) calculations indicate that the HOMO-LUMO energy gap (HLG) of the h-SiC nanosheet declines significantly from 2.543 to 1.492 eV upon the adsorption of the INH molecule, which causes an electrical conductivity increase and then produces an electrical signal. The signal is linked to the existence of INH, demonstrating that h-SiC may be an appropriate sensor for INH sensing. The decrease in HLG for the interaction of INH and h-SiC is the uppermost (up to 41%) representing the uppermost sensitivity, whereas the sensitivity trend is σ(h-SiC) > σ(h-AlN) > σ(h-BN). Quantum theory of atoms in molecules (QTAIM) investigations is employed to scrutinize the nature of the INH/nanosheet interactions. The QTAIM analysis reveals that the interaction of the INH molecule and h-SiC has a partially covalent nature, while INH/h-AlN model electrostatic interaction occurs in the system and noncovalent and electrostatic interaction for the INH/h-BN model. Finally, the state-of-the-art DFT-MD simulations utilized in this study can mimic ambient conditions. The results obtained from the MD simulation show that it takes more time to bond the INH drug and h-SiC, and the INH/h-SiC system becomes stable. The results of the current research demonstrate the potential of h-SiC as a suitable sensor and drug delivery platform for INH drugs to remedy tuberculosis.

Isoniazid hair drug levels among TB patients as a tool to monitor adherence, exposure, and TB treatment outcomes and its acceptability in a multicultural setting. A narrative review.

Accumulation of chemicals including drugs in hair has been used in forensic investigations. Studies have reported isoniazid drug levels in the hair of TB patients. To review literature for evidence on isoniazid hair drug levels as a tool to monitor adherence, exposure, and TB treatment outcomes and the acceptability of using human hair for medical testing. We reviewed literature through Pubmed, Embase, Medline, google scholar, and google grey literature. The search terms focused on isoniazid/TB hair drug levels, adherence, treatment outcomes, and acceptability of using hair for medical testing. We kept refining our search terms at each step of our search. The initial search yielded 186859 articles, which dropped to 88 after removing duplicates and irrelevant articles and eventually to 14 on further refining our search terms. On full review,2 out of 14 and 1 out of 14 articles touched the area of Isoniazid hair drug levels; adherence, exposure, TB treatment outcomes, and acceptability respectively. Further scrutiny showed that none of the articles had addressed our research question. Literature on Isoniazid hair drug levels among TB patients as a tool to monitor adherence, exposure, and TB treatment outcomes, and its acceptability is limited and more research is needed.

Synthesis and antituberculosis activity of new 5-alkynyl derivatives of 2-thiouridine: application of new scaffold

We herein describe new potent inhibitors of mycobacteria based on 5-substituted 2-thiouridine derivatives. A series of new 5-alkynyl-substituted 2-thiouridine derivatives were synthesized via palladium-catalysed Sonogashira cross-coupling reaction of 5-iodo-2-thiopyrimidine base with terminal acetylenes with good yields in DMF at room temperature. It was found that sulfur atom in C2 position of pyrimidine ring had no impact on yields of target compounds. All obtained compounds were evaluated for their antimycobacterial activity against Mycobacetrium bovis and Mycobacterium tuberculosis at concentrations of 0.1-100 µg/ml using MABA test. Synthesized nucleosides showed high antimycobacterial activity against Mycobacterium bovis and Mycobacteri um tuberculosis. The obtained MIC50 values of 2-thionucleosides 14, 15 and 16 (0.28-0.75 µg/ml) significantly exceed characteristics of reference drug rifampicin, D-cycloserine and isoniazid, which gives prerequisites for further more detailed studies.

Proficiency testing for drug susceptibility testing of Mycobacterium tuberculosis complex using commercial broth microdilution plate in China in 2021

The characteristic and performance of Broth microdilution (BMD) plates for drug susceptibility of Mycobacterium tuberculosis have not been systematically evaluated in China. This study was designed to review the key information and assess the performance of BMD plates by analysis of proficiency testing results. We retrospectively analysed the proficiency testing results of phenotypic drug susceptibility testing (PT-DST) of 45 laboratories using BMD plates in China in 2021. Critical information, such as drug layout, concentration range of each drug, plate storage conditions and duration, operating procedures, and interpretation criteria for binary results were compared. The performance was also analysed. Eight types of BMD plates produced by four manufactures were reported. The drug layout, number of drugs on plates, and concentration range varied a lot between different plates. The total sensitivity and specificity of BMD plates for drug susceptibility of Mycobacterium tuberculosis to ten drugs (isoniazid (INH), rifampin (RIF), kanamycin (KAM), amikacin (AM), levofloxacin (LFX), moxifloxacin (MFX), bedaquiline (BDQ), linezolid (LZD), clofazimine (CFZ), and delamanid (DLM)) were 93.9% (95% CI 92.-94.9) and 99.1% (95% CI 98.8-99.3), respectively. The lowest sensitivity was 84.8% (95% CI 80.3-88.4) for LFX and 86.4% (95% CI 82.5-89.6) for MFX, or 87.5% (95% CI 84.2-90.2) for Y1 plate and 87.9% (95% CI 83.5-91.1) for T plate. The lowest specificity was 94.4% (95% CI 91.4-96.4) for DLM, or 97.9% (95% CI 96.8-98.7) for B3 plate. Commercial BMD plates in China showed varied drug layouts and operational procedures, indicating the urgency of standardization. The lower performance for some drugs showed the low quality of the plates utilized or lack of proficiency of lab staffs in operating and interpreting results.

Synthesis and Antitubercular Activity of New 5-Alkynyl Derivatives of 2-Thiouridine

New efficient mycobacterial inhibitors based on 5-substituted 2-thiouridine derivatives have been described. A series of new 5-alkynyl-substituted 2-thiouridines have been synthesized in good yields by the palladium-catalyzed Sonogashira cross-coupling of 5-iodo-2-thiopyrimidine base with terminal alkynes in DMF at room temperature. The presence of a sulfur atm at C2 of the pyrimidine ring has been shown not to affect the yield of the target compounds. The synthesized 2-thiouridine derivatives were evaluated for their antimyco­bacterial activity against Mycobacterium bovis and Mycobacterium tuberculosis at concentrations of 0.1 to 100 μg/mL using microplate Alamar Blue assay (MABA). The compounds showed high antimycobacterial activity against both tested strains. The MIC50 values for 2-thionucleosides 14–16 (0.28–0.75 μg/mL) were much superior to those of the reference drugs rifampicin, D-cycloserine, and isoniazid, which makes these compounds promising for further more detailed study.

1897. Therapeutic Drug Monitoring in CSF and Plasma in Tuberculous Meningitis:Correlation with Disease Outcome

Abstract Background Tuberculous meningitis (TBM) is a serious form of extra-pulmonary tuberculosis with significant morbidity and mortality. TBM patients are treated with pulmonary tuberculosis regimen, often requiring extension for 1 year or longer. Current study was designed to find any association of CSF and blood levels of anti-tubercular drugs with treatment response in patients with tuberculous meningitis using therapeutic drug monitoring. Pharmacokinetic Parameters of Rifampicin and Isoniazid in CSF and Plasma Methods A prospective observational study was conducted in a tertiary care institute in North India among clinic-radiologically and/or microbiologically diagnosed TBM patients. Plasma and CSF levels of anti TB drugs (rifampicin, isoniazid, pyrazinamide and ethambutol) were determined using Liquid Chromatography Mass Spectrometry technology at 1 week and 1 month (follow up) after initiating treatment. The primary outcome assessed was association of drug levels with treatment response. The secondary outcomes assessed were association of drug levels with treatment duration/alteration, patient demographic profile, comorbidities and adverse effects. Patients were followed-up till treatment completion. Results A total of 40 patients with TBM were recruited. All received daily weight-based doses of anti TB drugs. Low Cmax of INH and rifampicin in plasma were observed in 60.5% & 42.1% of observations respectively. In CSF, low Cmax of INH and rifampicin were observed in 77.6% & 82.9% of observations respectively. The concentrations of INH (4 hours after drug intake) during follow up were significantly lower among patients with poor response, at 1 month (p=0.008) & 6 months (p=0.009). Similarly, low Cmax & CSF levels of INH at follow up sampling were significantly associated with poor response at 6 months of therapy (p= 0.022 & 0.042 respectively). Conclusion Low plasma and CSF concentrations of isoniazid were associated with a poor response to treatment in patients with TBM. Therapeutic drug monitoring can guide dose modification of ATT to achieve target concentrations in patients with TBM and facilitate optimal treatment outcomes. Higher dose INH can be considered in TBM treatment regimen for better outcome. Disclosures All Authors: No reported disclosures

DISCOVERY OF NEW NAPHTHYRIDINE HYBRIDS AGAINST ENOYL-ACP REDUCTASE (InhA) PROTEIN TARGET OF MYCOBACTERIUM TUBERCULOSIS: MOLECULAR DOCKING, MOLECULAR DYNAMICS SIMULATIONS STUDIES

Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) and remains a significant global public health concern, with many new cases reported annually. Despite advancements in TB treatment and control, the emergence of drug-resistant strains has presented a considerable challenge to eradication efforts. One crucial area that necessitates further research in antituberculosis is the development of effective treatments for drug-resistant strains, particularly multidrug resistance tuberculosis (MDR-TB), extensively drug-resistant tuberculosis (XDR-TB), and totally drug–resistant tuberculosis (TDR-TB). The limited and often unsatisfactory treatment options available for drug-resistant strains require the exploration of novel drugs and treatment regimens to combat this escalating issue. This study focuses on designing and developing a series of new 1,8-naphthyridine derivatives for their potential antitubercular activity. The compounds were designed and evaluated through in-silico screening using Molinspiration Cheminformatics, Osiris Property Explorer, AdmetSAR, and SwissADME. The initial filtering process identified the top 16 hybrids, which were then subjected to docking using the AutoDock tool. These compounds' binding energies were higher than the standard drug isoniazid, indicating a potentially more substantial interaction with the target. Based on the promising in silico and docking results, further investigations were conducted on the top 3 compounds, namely ST03, ST09, and ST14. To assess the stability and binding energies observed during the initial docking process, molecular dynamics simulations were performed over a 100 ns period. Both the docking and simulation studies consistently demonstrated that the 1,8-naphthyridine hybrid ST09 exhibited stable and efficient binding energies, suggesting its potential as an effective antituberculosis agent.

Molecular identification of multiple drug resistance (MDR) strain of Mycobacterium tuberculosis.

Isoniazid and rifampin are the first -line drugs against Mycobacterium tuberculosis. Resistance to these important drugs is a serious threat to human public health. Therefore, this study aimed at molecular detection of resistance to these valuable drugs. In this descriptive cross-sectional study, 111 non - duplicated clinical samples including sputum and Bronchoalveolar lavage (BAL) samples were collected from patients referred to the Ardabil Health Center between 2017 and 2020. The samples were first examined by microscopic method, then their DNA was extracted using the boiling method. Specific primers and MAS-PCR method were employed for the detection resistance to isoniazid and rifampin drugs and identification of MDR strain. of 111 specimens, 15.3% belonged to NTM. In total, the resistance rate to isoniazid and rifampin was 17% and 27% respectively while the resistance rate to isoniazid and rifampin among NTM was 61.54% and 38.46%. In our study, the prevalence of resistance to isoniazid and rifampin among Mycobacterium tuberculosis complex(MTC) and non-tuberculous mycobacteria(NTM) was investigated using the MAS-PCR method. This work highlighted the high anti- tuberculosis resistance rate among NTM compared to MTC strains.

EXTENT OF HEPATOTOXICITY OF ANTI-TUBERCULOSIS DRUGS USED IN PAKISTAN: A CROSS-SECTIONAL STUDY

Introduction: Tuberculosis is an infectious disease with high rates of infection and mortality throughout the world, but its spread is greater in developing countries, and its control is difficult. It is known that the most common side reaction of drug treatment for tuberculosis is hepatotoxicity resulting from the drugs, which negatively affects adherence to treatment as a result of patients not continuing to use it. Objective:This study aimed to determine the extent of hepatotoxicity as a result of drug treatment for tuberculosis. Methods: The study is a cross-sectional study conducted on TB patients undergoing TB treatment in a general hospital in Islamabad, Pakistan. A data collection form was used to obtain demographic and treatment data. The hepatotoxicity of TB drug therapy was evaluated by performing liver function tests (LFTs).Study duration was of 4 months. Results: The study showed that out of 100 tuberculosis patients, 55 patients were hepatotoxic. Hepatotoxic population includes 26% males and 29% females including almost 10% children either male or female. The maximun hepatotoxicity was observed in the patients undergoing combination therapy. Around 3-5 % patients showed that the Serum-GlutamicPyruvic-Transaminase (SGPT) values more than 2 times of their normal values. While other 50% showed hepatotoxicity 1-2 times of their normal values. Most of the patients found were in the age group ranging from 35-60 years. The main drugs used in tuberculosis treatment were: Isoniazid, Rifampicin, Pyrazinamide, Ethambutal. Conclusion:The rate of hepatotoxicity in TB patients on anti-TB treatment was high. The current study concluded that the more we move towards a greater number of drugs in combination, the greater the extent and chance of hepatotoxicity. The combination of three anti-tuberculosis drugs (isoniazid, rifampicin, and pyrazinamide) resulted in maximum hepatotoxicity. Peer Review History: Received: 21 August 2023; Revised: 18 September; Accepted: 19 October, Available online: 15 November 2023 Academic Editor: Dr. Marwa A. A. Fayed, University of Sadat City, Egypt, maafayed@gmail.com Received file: Reviewer's Comments: Average Peer review marks at initial stage: 6.0/10 Average Peer review marks at publication stage: 7.0/10 Reviewers: Dr. Owanaro Peter, Nigeria, Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Niger Delta University, Wilberforce Island, Bayelsa State, Nigeria. owonaropeter@gmail.com Prof. Hassan A.H. Al-Shamahy, Sana'a University, Yemen, shmahe@yemen.net.ye Dr. Sheikh Abdul Khaliq, Department of Pharmacy Practice, Faculty of Pharmacy, Hamdard University, Karachi, Pakistan, drwadhsheikh1974@gmail.com

Whole-Genome Sequencing Predicting Phenotypic Antitubercular Drug Resistance: Meta-analysis.

For simultaneous prediction of phenotypic drug susceptibility test (pDST) for multiple antituberculosis drugs, the whole genome sequencing (WGS) data can be analyzed using either a catalog-based approach, wherein 1 causative mutation suggests resistance, (eg, World Health Organization catalog) or noncatalog-based approach using complicated algorithm (eg, TB-profiler, machine learning). The aim was to estimate the predictive ability of WGS-based tests with pDST as the reference, and to compare the 2 approaches. Following a systematic literature search, the diagnostic test accuracies for 14 drugs were pooled using a random-effect bivariate model. Of 779 articles, 44 with 16 821 specimens for meta-analysis and 13 not for meta-analysis were included. The areas under summary receiver operating characteristic curve suggested test accuracy was excellent (0.97-1.00) for 2 drugs (isoniazid 0.975, rifampicin 0.975), very good (0.93-0.97) for 8 drugs (pyrazinamide 0.946, streptomycin 0.952, amikacin 0.968, kanamycin 0.963, capreomycin 0.965, para-aminosalicylic acid 0.959, levofloxacin 0.960, ofloxacin 0.958), and good (0.75-0.93) for 4 drugs (ethambutol 0.926, moxifloxacin 0.896, ethionamide 0.878, prothionamide 0.908). The noncatalog-based and catalog-based approaches had similar ability for all drugs. WGS accurately identifies isoniazid and rifampicin resistance. For most drugs, positive WGS results reliably predict pDST positive. The 2 approaches had similar ability. UMIN-ID UMIN000049276.

Development of a HPLC Method for Analysis of a Combination of Clofazimine, Isoniazid, Pyrazinamide, and Rifampicin Incorporated into a Dermal Self-Double-Emulsifying Drug Delivery System.

We describe the development and validation of a new high performance liquid chromatography (HPLC) method for analysis of a combination of the first-line anti-tubercular drugs isoniazid, pyrazinamide, and rifampicin together with clofazimine. This is a unique challenge since clofazimine and rifampicin are relatively highly lipophilic drugs, whereas isoniazid and pyrazinamide are considerably more hydrophilic. Thus, clear separation of peaks and quantification of four individual drugs can present difficulties during the development of an analytical method. Detection was established at two wavelengths-254 nm for isoniazid and pyrazinamide and 320 nm for clofazimine and rifampicin. Gradient elution was employed using 0.1% aqueous formic acid (A) and acetonitrile (B); clear separation of the four drugs was achieved within 10 min. A linear relationship was indicated by a correlation coefficient (r2) of 0.9999 for each anti-tubercular drug, respectively. The limit of detection (LOD) for the individual drugs was 0.70 µg/mL (isoniazid), 0.30 µg/mL (pyrazinamide), 0.20 µg/mL (rifampicin) and 0.20 µg/mL (clofazimine). Precision experiments rendered a mean recovery percentage of 101.25% (isoniazid), 98.70% (pyrazinamide), 99.68% (rifampicin) and 97.14% (clofazimine). This HPLC method was validated and is reliable, repeatable, and accurate for the purpose of conducting simultaneous HPLC analyses of the four anti-tubercular drugs.

Molecular interaction studies of antituberculosis drug Isoniazid in aq. β-cyclodextrin solution: A volumetric, spectroscopic and molecular docking approach

Volumetric and compressibility investigations are crucial to understanding the molecular interactions prevailing between various components of solutions. At distinct temperatures and ambient pressure (P = 0.1 MPa), the effect of β-cyclodextrin on the antituberculosis drug Isoniazid (INH) was studied at concentrations ranging from 0.0304-0.2698 mol.kg−1. Some thermodynamic properties of the drug Isoniazid, viz., limiting apparent molar volume and limiting compressibility (V°ϕ and K°S,ϕ) are derived from the appropriate density (ρ) and ultrasonic velocity (u) data, with experimental slopes Sv and Sk describing solute–solute interactional parameters at infinite dilution. Furthermore, transfer properties of drug, such as limiting transfer volume (ΔtrV°ϕ) and limiting transfer compressibility (Δtr K°S,ϕ) of drug, reveal key information regarding the interaction of drug with a solvent or a cosolute. The hydration number (nH) was computed to figure out the hydration behaviour of the studied drug in both the mediums. The encapsulation of isoniazid drug in the hydrophobic region of cosolute (β-cyclodextrin) in the solution phase was evaluated using 1H NMR titration. Additionally, theoretical molecular docking was employed to determine the possible conformation and binding energy of the non-covalent inclusion complex.

Pharmacokinetics and safety of first-line tuberculosis drugs rifampin, isoniazid, ethambutol, and pyrazinamide during pregnancy and postpartum: results from IMPAACT P1026s.

Physiological changes during pregnancy may alter the pharmacokinetics (PK) of antituberculosis drugs. The International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1026s was a multicenter, phase IV, observational, prospective PK and safety study of antiretroviral and antituberculosis drugs administered as part of clinical care in pregnant persons living with and without HIV. We assessed the effects of pregnancy on rifampin, isoniazid, ethambutol, and pyrazinamide PK in pregnant and postpartum (PP) persons without HIV treated for drug-susceptible tuberculosis disease. Daily antituberculosis treatment was prescribed following World Health Organization-recommended weight-band dosing guidelines. Steady-state 12-hour PK profiles of rifampin, isoniazid, ethambutol, and pyrazinamide were performed during second trimester (2T), third trimester (3T), and 2-8 of weeks PP. PK parameters were characterized using noncompartmental analysis, and comparisons were made using geometric mean ratios (GMRs) with 90% confidence intervals (CI). Twenty-seven participants were included: 11 African, 9 Asian, 3 Hispanic, and 4 mixed descent. PK data were available for 17, 21, and 14 participants in 2T, 3T, and PP, respectively. Rifampin and pyrazinamide AUC0-24 and C max in pregnancy were comparable to PP with the GMR between 0.80 and 1.25. Compared to PP, isoniazid AUC0-24 was 25% lower and C max was 23% lower in 3T. Ethambutol AUC0-24 was 39% lower in 3T but limited by a low PP sample size. In summary, isoniazid and ethambutol concentrations were lower during pregnancy compared to PP concentrations, while rifampin and pyrazinamide concentrations were similar. However, the median AUC0-24 for rifampin, isoniazid, and pyrazinamide met the therapeutic targets. The clinical impact of lower isoniazid and ethambutol exposure during pregnancy needs to be determined.

Adjunct Therapy With All-trans-Retinoic Acid Improves Therapeutic Efficacy Through Immunomodulation While Treating Tuberculosis With Antibiotics in Mice.

Tuberculosis is the second leading infectious killer after coronavirus disease 2019 (COVID-19). Standard antitubercular drugs exhibit various limitations like toxicity, long treatment regimens, and lack of effect against dormant and drug-resistant organisms. Here, we report that all-trans-retinoic acid (ATRA) improves Mycobacterium tuberculosis clearance in mice during treatment with the antitubercular drug isoniazid. Interestingly, ATRA promoted activities of lysosomes and mitochondria, and production of various inflammatory mediators in macrophages. Furthermore, ATRA upregulated the expression of genes of lipid metabolism pathways in macrophages. We demonstrated that ATRA activated the MEK/ERK pathway in macrophages in vitro and MEK/ERK and p38 MAPK pathways in mice. Finally, ATRA induced both Th1 and Th17 responses in lungs and spleens of M. tuberculosis-infected mice. Together, these data indicate that ATRA provides beneficial adjunct therapeutic value by modulating MEK/ERK and p38 MAPK pathways and thus warrants further testing for human use.

Exploring the potential of MIL-53(Fe) as a fluorescent probe for the highly selective and sensitive detection of anti-tuberculosis drug—Isoniazid

Ecosystem and human health can both be catastrophically harmed by overuse of anti-tuberculosis drug, isoniazid. Within this frame of reference, an Fe-based metal organic framework (MIL-53(Fe)) was developed via hydrothermal route to successfully recognise and detect, isoniazid antibiotic, using fluorescence sensing. The structural, morphological and other important property insights of MIL-53(Fe) were gained using various techniques like FT-IR, XRD, FE-SEM, BET, TGA and VSM. The developed fluorescence probe exhibited fluorescence enhancement with the incremental addition of isoniazid antibiotic, in the range of 0.1 to 7.0 µM. The limit of detection (LOD) value was found to be 0.25 µM under optimal sensing conditions. MIL-53(Fe) demonstrated high selectivity and specificity for the detection of isoniazid. In addition, the sensor displayed excellent performance in reproducibility, repeatability and real water studies.

New Thiophenyl-pyrazolyl-thiazole Hybrids as DHFR Inhibitors: Design, Synthesis, Antimicrobial Evaluation, Molecular Modeling, and Biodistribution Studies.

The antibiotic resistance problems constitute a considerable threat to human health worldwide; thus, the discovery of new antimicrobial candidates to conquer this issue is an imperative requirement. From this view, new thiophenyl-pyrazolyl-thiazole hybrids 3-10 were synthesized and screened for their antibacterial efficiency versus Gram - and Gram + bacterial strains compared to the reference drug amoxicillin. It was noticed that the new hybrids displayed significant antibacterial efficacy versus Gram - bacteria, especially against Pseudomonas aeruginosa. Also, all the screened candidates demonstrated a noticeable antifungal effect against Candida albicans (MICs = 3.9-125 μg/mL) relative to fluconazole (MIC = 250 μg/mL). Moreover, the new hybrids were investigated for their antituberculosis potency against Mycobacterium tuberculosis (RCMB 010126). Derivatives 4c, 6b, 8b, 9b, and 10b demonstrated prominent antituberculosis efficiency (MICs = 0.12-1.95 μg/mL) compared with the reference drug isoniazid (MIC = 0.12 μg/mL). The latter derivatives were further assessed for their inhibitory potency versus M. tuberculosis DHFR enzyme. The compounds 4c, 6b and 10b presented a remarkable suppression effect with IC50 values of 4.21, 5.70, and 10.59 μM, respectively, compared to that of trimethoprim (IC50 = 6.23 μM). Furthermore, biodistribution profile using radiolabeling way revealed a perceived uptake of 131I-compound 6b into infection induced models. The docking study for the new hybrids 4c, 6b, 8b, 9b and 10b was performed to illustrate the various binding modes with Mtb DHFR enzyme. In silico ADMET studies for the most potent inhibitors 4c, 6b and 10b were also accomplished to predict their pharmacokinetic and physicochemical features.

Usefulness of truenat-derived DNA from extrapulmonary specimens in direct detection of drug resistant tuberculosis by line probe assay

Objectives: Isoniazid (INH) and second-line drug resistance (DR) detection through line probe assay (LPA) takes long in extrapulmonary (EP) specimens because culture growth needs to be obtained to perform deoxyribonucleic acid (DNA) extraction due to the paucibacillary nature of these specimens. Knowing the DR pattern at the earliest is key to success of the treatment. Delay in appropriate tuberculosis (TB) treatment in EP TB patients runs the risk of DR amplification, significant disease damage, and patient loss to follow-up. Here, LPA was attempted on truenat-derived DNA elute from EP specimens, which, in routine, is discarded after the truenat test, to determine drug sensitivity test (DST) for INH and, where necessary, for second-line drugs (Fluoroquinolones, Kanamycin, amikacin, and capreomycin). Material and Methods: Truenat, acid-fast bacilli culture, and fluorescent microscopy were performed on all EP samples that were received at the laboratory during June–September 2022. DNA elute that was left over from 59 truenat Mycobacterium tuberculosis (MTB) positive EP samples were subjected to Genotype MTBDR plus Ver 2.0 assay. Results: MTBDR plus assay (DNA elute) detected MTB and rifampicin (RIF) and INH DST in 47 samples (79.6%) having truenat MTB count of 7.8 × 102 colony-forming unit/milliliter and above. It also detected RIF DST in 65.2% truenat RIF indeterminate samples and DST for both RIF and INH in 60% of culture negative EP specimens. DST results by LPA (DNA elute) completely concorded with standard indirect LPA (on 21 culture isolates from smear-negative specimens). The MTBDRsl yield was however relatively low (11.1%), although second line LPA (SLLPA) was performed only on 9 first-line DR samples. Conclusions: Left-over truenat-derived DNA elute is a significant sample by-product that can significantly speed up and increase the yield of determination of MTB DST in EP samples for RIF and INH, the most critical drugs for TB treatment.

Microwave-assisted rapid catalytic degradation of isoniazid drug using polythiophene/ZnFe2O4 organic-inorganic hybrids

This present work reports for the first time, microwave-assisted catalytic degradation of isoniazid drug using organic–inorganic hybrids of polythiophene (PTh) decorated ZnFe2O4 nanoparticles. The hybrids were characterized using fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD) and scanning electron microscopy along with energy dispersive spectra (SEM-EDS). The nanohybrids were used as catalysts for the degradation of isoniazid (ISN) drug under microwave irradiation. Almost 94% degradation of isoniazid was attained within 24 min using 100 mg of the catalyst. The degraded drug fragments were analyzed using LCMS and a tentative mechanism of degradation was proposed.