Search Results (553)

Pulmonary delivery of anti-tuberculosis drugs has emerged as a promising alternative for increasing local drug concentrations whilst minimising side effects. Natural polymers—polysaccharides capable of forming polyelectrolyte complexes (PECs) through electrostatic interactions—show great promise in this field. In this study, mucoadhesive chitosan-gellan gum nanoparticles were developed for the controlled release of isoniazid using the polyelectrolyte complex coacervation method. Parameters such as the chitosan-to-gellan gum ratio and the medium pH were investigated to achieve suitable particle size, polydispersity, surface charge, drug loading and encapsulation efficiency. The morphology of the produced nanoparticles was determined using transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA), which confirmed the formation of nanoscale spherical particles. The mucoadhesive properties were tested on ovine lung tissue using fluorescence retention analysis, whilst in vitro drug release was studied under physiological conditions. Antimycobacterial activity against Mycobacterium tuberculosis H37Rv was assessed using the Mycobacteria Growth Indicator Tube (MGIT) system, followed by subculturing on Löwenstein–Jensen medium. The produced nanoparticles exhibited high mucoadhesion, maintaining prolonged retention on lung tissue. Drug release showed an initial burst followed by sustained release over 24 h. These results demonstrate that CSGG–INH nanoparticles possess sustained drug release, good mucoadhesion to the lungs and high antimycobacterial activity, supporting their further development as potential carriers for pulmonary delivery of anti-tuberculosis drugs. Full article

Background: Nontuberculous mycobacterial pulmonary disease (NTM-PD) and pulmonary tuberculosis (PTB) present with similar clinical and radiological features, frequently leading to misdiagnosis. This study aimed to compare NTM-PD with extrapulmonary NTM disease (ENTM) and PTB and to develop a predictive model for early differentiation. Methods: We retrospectively analyzed 473 NTM patients (340 NTM-PD, 112 ENTM, 21 disseminated) and 218 PTB patients treated between January 2008 and December 2024. A diagnostic model was developed using the Least Absolute Shrinkage and Selection Operator (LASSO) regression algorithm and multivariate logistic regression, with internal validation via 1000 bootstrap resamples and a pre-split validation cohort. Performance was evaluated by the area under the receiver operating characteristic curve (AUC), calibration curves, and decision curve analysis. Results: Compared to ENTM, NTM-PD patients were older and had lower BMI, with bronchiectasis (OR = 24.86) and prior PTB history (OR = 7.58) as the strongest risk factors. Relative to PTB, NTM-PD patients were more often female and older, with more bronchiectasis and mucus plugs on imaging, while PTB showed more pleural thickening and effusion. NTM isolates exhibited high resistance to first-line anti-TB drugs but maintained susceptibility to macrolides and amikacin. The nine-predictor nomogram achieved AUCs of 0.758 (training) and 0.731 (validation), with calibration and decision curve analysis confirming clinical utility. Conclusions: NTM-PD and PTB exhibit distinct clinical, radiological, and microbiological profiles. The nomogram offers a useful preliminary screening tool for early differentiation, though external validation in multicenter studies is warranted. Full article

Tuberculosis (TB) remains one of the most significant global public health challenges, as it represents the world’s leading infectious cause of death. The clinical efficacy of currently available anti-TB drugs is increasingly compromised due to the growing prevalence of antibiotic-resistant strains, side effects, and prolonged treatment times. This scenario highlights the urgent need to identify new anti-TB drugs with alternative mechanisms of action and improved anti-TB activity and bioavailability. In this context, natural products derived from microorganisms represent a key source of chemical diversity for drug discovery. Actinomycetes, fungi, and other environmental microbes produce a wide range of secondary metabolites with broad antimicrobial activity. These compounds can interfere with essential bacterial structures and processes, including membrane integrity, redox homeostasis, protein synthesis, and DNA replication. This review aims to evaluate new microbial natural products for their antibacterial activity, focusing on their efficacy, mechanisms of action, chemical nature, and potential clinical applications, with the aim of informing the development of new anti-TB agents. Full article

The present study investigates the physicochemical behavior of the first-line anti-tuberculosis drugs isoniazid (INH) and ethambutol, in the form of dihydrochloride (E·(HCl)₂), in aqueous solutions containing the synthetic macrocyclic resorcinarene, C-tetra(propyl)resorcin[4]tetrasulfonate (Na₄PRA) at 298.15 K. Taylor dispersion experiments were conducted to determine the ternary diffusion coefficients of these systems, offering valuable insights into their transport properties. Non-zero cross-diffusion coefficients (${\mathit{D}}_{12}$ and ${\mathit{D}}_{21}$) demonstrate significant coupled transport, collectively indicating interactions between these antibiotics and the resorcinarene host. This behavior is highly consistent with the formation of a host–guest complex. These diffusion measurements were complemented by NMR spectroscopy, which confirmed the formation of host–guest complexes between the respective drugs and this resorcinarene, Na₄PRA. Full article

Background/Objectives: Zoonotic tuberculosis (TB) remains a persistent public health challenge worldwide. It is particularly common in settings with close human–livestock–environment interactions. In Tanzania, progress toward TB control is increasingly threatened by multidrug-resistant tuberculosis (MDR-TB), yet genomic data from regions characterized by pastoralist and mining activities remain scarce. This study employed whole-genome sequencing (WGS) to characterize M. tuberculosis complex (MTBC) strains circulating among human and cattle populations in the Manyara region of northern Tanzania, with a focus on resistance-associated mutations and phylogenetic relationships. Methods: This cross-sectional study was conducted between September 2024 and February 2025. A total of 178 presumptive human TB cases provided sputum samples. From cattle, 161 samples were collected (110 milk samples and 51 lymph node aspirates), with each animal contributing only one type of sample. Specimen were analyzed using GeneXpert MTB/RIF, Lowenstein–Jensen culture, and WGS. Phylogenetic reconstruction was performed using SNP-based methods and IQ-TREE2 version 2.2.0. Results: Among human participants, 14 (7.8%) sputum samples were GeneXpert positive and were confirmed as members of MTBC by LJ culture. In cattle, one (0.62%) lymph node aspirate was positive for MTBC. Significant predictors of MTBC positivity included previous TB history, weight loss, and occupation involving mining and cattle keeping. WGS of five human isolates identified Lineages 1, 3, and 4. One isolate (Sample 98) harbored mutations associated with XDR-TB. Conclusions: WGS revealed M. tuberculosis Lineages 1, 3 and 4 circulating in the Manyara region, with diverse genetic mutations conferring with resistance to first- and second-line anti-TB drugs. These findings highlight the importance of integrated genomic surveillance to monitor drug resistance patterns in Tanzania and similar settings across human and animal populations. Full article

Background/Objectives: Phenotypic drug tolerance, distinct from genetic resistance, allows Mycobacterium tuberculosis (Mtb) to survive prolonged antibiotic exposure and contributes to treatment failure and relapse. The trehalose recycling pathway, mediated by the LpqY-SugABC transporter, has been implicated as a metabolic “escape” mechanism that sustains Mtb viability under antibiotic and nutrient-limiting stress, making it an attractive target for adjunctive, tolerance-breaking therapeutics. Methods and Results: Here, we conducted a high-throughput phenotypic screen of 50,000 compounds from chemically diverse libraries, using a carbon source-restricted assay that forces Mtb to rely on trehalose uptake for growth, to identify small-molecule inhibitors of this pathway. This approach yielded 23 confirmed hits in Mtb, spanning several chemical scaffolds, including thioureas, propanamides, benzamides, and carboxamides. Using an isogenic set of Mtb wild-type, LpqY-SugABC transposon knockout, and complemented strains, we confirmed that the genetic loss of transporter loss reproduces accelerated killing by isoniazid, rifampicin, and bedaquiline, but not moxifloxacin, and that loss of trehalose recycling sensitizes mycobacteria to oxidative stress. Using orthogonal functional assays, fluorescent trehalose probe (FITC-tre) uptake inhibition and H₂O₂ hypersensitization, thiourea-containing compounds emerged as the candidates most consistent with transporter-specific activity, phenocopying the effects of genetic LpqY-SugABC loss, while biochemical assays against recombinant trehalase (Rv2402) excluded downstream enzymatic inhibition as their mechanism of action. In addition, several hits potentiated rifampicin-mediated killing of intracellular Mtb in THP-1 macrophages, in some cases reducing bacterial burden below levels achieved by monotherapy. Conclusions: These findings indicate that the trehalose recycling pathway is functionally druggable by small molecules identified through unbiased phenotypic screening and nominate thiourea- and propanamide-based scaffolds as priority candidates for further mechanistic characterization, including direct target-engagement studies, and optimization as adjunctive anti-tuberculosis agents targeting drug-tolerant Mtb populations. Full article

Tuberculosis (TB) continues to be a significant public health challenge in Europe, despite a sustained decline in disease incidence over recent decades. This narrative review briefly traces the historical development of TB diagnosis and focuses on the evolution of TB control protocols from the early twentieth century to the present across Europe, through a longitudinal comparative analysis of its geographical regions. A literature search was conducted using publications, guidelines, and surveillance reports from the World Health Organization (WHO), the European Centre for Disease Prevention and Control (ECDC), and national public health authorities. The analysis follows a geographical framework encompassing Eastern, Western, Northern, and Southern Europe, reflecting historical, socioeconomic, and healthcare system differences. This study presents the transition from traditional diagnostic approaches based on clinical assessment, chest radiography, and smear microscopy to modern molecular and immunological techniques, including Xpert MTB/RIF assays and interferon-gamma release assays (IGRAs). Similarly, treatment strategies have evolved from sanatorium-based supportive care to standardized, evidence-based short-course regimens employing first- and second-line anti-TB drugs. However, marked regional differences remain in the implementation of contemporary protocols. Western and Northern European countries have largely adopted advanced diagnostic technologies and comprehensive surveillance systems and are approaching TB elimination targets. In contrast, Eastern Europe continues to bear a disproportionate disease burden, driven by multidrug-resistant TB, HIV co-infection, and socioeconomic disparities. TB control protocols in Southern Europe are progressively converging with those of Western Europe through the adoption of modern diagnostic approaches, standardized treatment regimens, and WHO-endorsed guidelines. The findings of this study underscore the need for greater harmonization of TB control protocols across Europe through an initiative coordinated by the ECDC/WHO. Accelerating progress toward TB elimination in the European Region will depend on expanding access to modern diagnostic technologies, implementing targeted interventions in high-burden settings, and strengthening cross-border collaboration through coordinated public health policies. Full article

Tuberculosis (TB) remains a major global health challenge, compounded by rising drug resistance. Traditional medicinal plants used for TB-related symptoms represent a valuable yet underexplored source of potential antimycobacterial agents. In this study, the phytochemical content and biological activities of Dombeya rotundifolia and Lippia javanica were evaluated, and antimycobacterial compounds were isolated through bioassay-guided fractionation. Plant leaves were collected, extracted with solvents of varying polarity, and screened for phenolics and flavonoids. Antioxidant activity was assessed using DPPH and ferric reducing power assays, antimycobacterial activity was tested against Mycobacterium smegmatis, anti-inflammatory activity was determined by the egg albumin denaturation method, and cytotoxicity was evaluated in THP-1 cells using the MTT assay. Extraction yields varied, with water extracts of L. javanica showing the highest yield and hexane extracts of D. rotundifolia the lowest. Both plants contained bioactive phytochemicals with measurable antioxidant activity, while acetone and dichloromethane extracts of D. rotundifolia displayed the strongest antimycobacterial activity with MIC values of 0.16 mg/mL. Cytotoxicity assays indicated moderate toxicity at higher extract concentrations. Bioassay-guided isolation led to the identification of two fatty acid fractions with tentative characterization, which showed notable antimycobacterial activity (MIC 0.25 mg/mL). These findings provide preliminary support for the ethnomedicinal use of D. rotundifolia in respiratory conditions traditionally associated with tuberculosis and suggest a potential contribution of its fatty acids to its observed antimycobacterial activity. Full article

The selective gas-phase oxidation of γ-picoline (γ-P) to isonicotinic acid (INA)—a key precursor for the anti-tuberculosis drug isoniazid—was investigated over a V–Mn oxide catalyst as a solvent-free, waste-minimizing alternative to conventional liquid-phase synthesis routes. XRD and Raman spectroscopy confirmed the formation of a stable manganese vanadate crystalline phase with a high concentration of terminal vanadyl groups (V=O), providing well-defined redox-active sites. Water vapour proved essential for sustainable process performance: at an optimal H₂O/substrate molar ratio of 98, γ-picoline conversion reached 94.8% with INA selectivity of 86.5%, eliminating the need for hazardous solvents or additives. NH₃-TPD and kinetic analysis revealed that water vapour acts as a competitive adsorbent at vanadium Lewis acid sites, accelerating target product desorption and suppressing deep oxidation to COx—directly reducing carbon waste. Long-term stability was assessed over 96 h of continuous operation: the 23.4% decline in specific surface area correlated with an equivalent reduction in total acidity, while pore diameter expansion from 2.07 to 3.25 nm mitigated diffusion limitations, partially compensating for deactivation. These findings establish the V–Mn oxide system as a promising green catalytic platform for upgrading petrochemical fractions into high-value pharmaceutical intermediates with reduced environmental impact. Full article

Chronic liver disease (CLD) constitutes a major global health burden, with high morbidity and mortality, limited treatment options for several etiologies, and an urgent need for novel therapeutic targets. Fibroblast growth factor 1 (FGF1) is a unique member of the FGF family capable of binding all four FGFR subtypes, thereby regulating multiple signaling pathways including PI3K/AKT, Ras/MAPK, and PLCγ, which are involved in metabolism, cell survival, proliferation, and tissue repair. Emerging evidence highlights the multifaceted and context-dependent roles of FGF1 in CLD. In drug-induced liver injury (DILI) caused by anti-tuberculosis drugs, acetaminophen, or doxorubicin, FGF1 confers protection by restoring bile acid homeostasis, reducing oxidative stress, inflammation, and apoptosis. In Metabolic dysfunction-associated steatotic liver disease (MASLD), FGF1 ameliorates hepatic steatosis, oxidative injury, and insulin resistance through downregulation of SREBP1, upregulation of PPARα, and activation of Nrf2-mediated antioxidant responses. Conversely, in primary sclerosing cholangitis (PSC), FGF1 aggravates ductular reaction, biliary senescence, and liver fibrosis via upregulation of SASP and TGF-β1, suggesting that inhibition of the FGF1/FGFR axis may be therapeutic. For alcohol-related liver disease (ALD), although direct experimental evidence is lacking, FGF1 is hypothesized to confer protection given its known activities against oxidative stress, lipid dysregulation, and cell death. Despite its promise, the mitogenic potential of FGF1 raises safety concerns; however, N-terminally modified FGF1 analogs (e.g., FGF1Δ) retain metabolic benefits with reduced proliferative activity. Collectively, FGF1 represents a versatile and disease-dependent regulator in CLD, warranting further mechanistic studies, safety evaluations, and development of targeted analogs as a novel therapeutic strategy for difficult-to-treat liver diseases. Full article

Identification of ligands targeting essential enzymes in Mycobacterium species remains an important strategy for anti-tuberculosis drug discovery. Here, a native mass spectrometry approach was employed using pooled 100-compound mixtures, enabling the direct detection of intact HPPK–ligand complexes in solution. Dual-mode MS acquisitions (low collision energy for complex detection and high collision energy for ligand confirmation), combined with an automated data analysis workflow, ensured robust identification of binding events from these complex samples. This strategy led to the identification of several HPPK-binding small molecules, all belonging to the dammarane triterpene glycoside (ginsenoside) class. Subsequent analysis of the hits revealed clear structure–affinity relationships, highlighting how specific aglycone modifications and glycosylation patterns influence binding to HPPK. Our findings expand the known chemical space of HPPK ligands and demonstrate the utility of native MS-based screening coupled with automated data analysis to uncover new ligand scaffolds for challenging enzyme targets. Full article

Phosphoribosyl transferase (Rv3806c) is a key enzyme in Mycobacterium tuberculosis. It is involved in the biosynthesis of decaprenylphosphoryl arabinofuranose, which is the sole donor of arabinofuranose residues in the biosynthesis of arabinogalactan and lipoarabinomannan. Inhibition of Rv3806c disrupts cell wall assembly, making it an attractive target for anti-tuberculosis drug development. In this study, a structure-based computational approach was employed to find natural inhibitors of Rv3806c. In silico ADMET filtration of 36,530 compounds from the Natural Products Atlas (NPAtlas) database and 105,909 compounds from the Bioactivity of Indian Medicinal Plants (BIMP) database yielded 285 and 553 compounds, respectively. Molecular docking analysis identified four compounds (NPA004179, NPA011911, BIMP003941, and BIMP004391) with binding affinities (−8.2, −7.5, −7.8, and −8.6 kcal/mol), respectively, stronger than the binding affinity of the native ligand (−7.2 kcal/mol). Molecular dynamics simulations demonstrated that all complexes exhibited low structural deviation, consistent hydrogen bonding, and stable protein–ligand compactness throughout the simulation period. MMPBSA analysis revealed thermodynamic stability of the Rv3806c–ligand complexes with binding energies ranging from (–14.91 to –26.30 kcal/mol). These computational findings may serve as a useful starting point for further optimization and experimental validation towards anti-tuberculosis therapeutics targeting Rv3806c. Full article

Background/Objectives: Reactive oxygen species (ROS) are key effectors of innate immunity but can also contribute to inflammation and tissue injury when their production is dysregulated. Although antibiotics are primarily selected for their antimicrobial activity, prolonged treatment may also influence host immune responses. However, the effects of anti-tuberculosis drugs on ROS production across innate immune cell subsets have not been assessed, especially not for novel drugs currently used against multi drug-resistant (MDR) tuberculosis (TB). Methods: Whole blood from healthy donors was incubated with seven antimycobacterial drugs used against MDR TB at sub-therapeutic, therapeutic, and supra-therapeutic concentrations. ROS production was quantified by flow cytometry using dihydrorhodamine 123 (DHR-123) in neutrophils, classical monocytes, and eosinophils under unstimulated conditions or following stimulation with Escherichia coli, fMLP, or PMA. Results: Bedaquiline and clofazimine decreased ROS production in neutrophils and classical monocytes across multiple stimuli (median values of Rh-123⁺ classical monocytes after E. coli stimulation without BDQ was 30.8% versus 24.9% with 1 µg/mL BDQ (p < 0.05, therapeutic concentration) and 31.3% without CFZ versus 19.2% with 1 µg/mL CFZ (p < 0.01, therapeutic concentration) in the same conditions). In contrast, levofloxacin and linezolid showed no detectable impact on ROS production in any cell population. Pretomanid uniquely induced a reduction in ROS generation in eosinophils and classical monocytes while sparing neutrophil oxidative burst activity, distinguishing it from other antibiotics tested (34.1% decrease in Rh-123 MFI of eosinophils between the control and PA 3 µg/mL after fMLP stimulation, p < 0.01, therapeutic concentration). Conclusions: These findings demonstrate that first line drugs against MDR TB display heterogeneous and cell type-specific effects on innate immune oxidative responses. Such differential effects on host immunity may have implications for both antimicrobial efficacy and inflammation control during tuberculosis treatment. Full article

In searching for novel molecules to act as antibacterial agents, particularly against Mycobacterium tuberculosis bacteria, three series of C5- and C6-substituted 1,2,3-triazine compounds were investigated: 1,2,3-triazine-4-carboxylate 1-oxide (series 1), 1,2,3-triazine-4-carboxylate (series 2), and 3,6-dihydro-1,2,3-triazine-4-carboxylate 1-oxide derivatives (series 3). Their structural elucidation was confirmed by ¹H-NMR, ¹³C-NMR, and HRMS. We determined their antibacterial activity (MIC value) using the MABA against the M. tuberculosis H37Rv strain, as well as their physicochemical and pharmacokinetic properties. Finally, to determine their potential mode of action, an inhibition assay against M. tuberculosis DNA gyrase was performed. Compounds 4-ethoxycarbonyl-5-(3-methoxyphenyl)-1,2,3-triazine (2l) and 4-ethoxycarbonyl-5 -(n-propyl)-1,2,3-triazine (3s) exhibited high activity against M. tuberculosis with MIC values < 5.90 µg/mL and selectivity index of 18.56 and 8.36, respectively. Additionally, compound 2m also exhibited anti-mycobacterial activity with MIC values < 10.0 µg/mL. However, none of the selected compounds inhibited the activity of M. tuberculosis DNA gyrase, suggesting that another drug target may be involved as a mode of action. These results encourage exploring the use of 1,2,3-triazine as a scaffold for the development of new anti-mycobacterium agents. Full article

Tuberculosis (TB) treatment is severely hampered by the rise in multi-drug-resistant strains and the prevalence of drug-induced toxicities. Host-Directed Therapies (HDTs) have emerged as a promising strategy to overcome these challenges by modulating innate immunity and circumventing Mycobacterium tuberculosis (Mtb) evasion mechanisms. A hallmark of Mtb pathogenesis is the arrest of phagosome maturation and the induction of host cell necrosis over protective apoptosis. In this study, we investigated the potential HDT effects of α-Lipoic acid (α-LA), a well-known antioxidant and metabolic cofactor, within an in vitro model of Mtb-infected THP-1 macrophages. Our findings indicate that α-LA treatment modulates the macrophage redox state and selectively promotes apoptosis in infected cells without increasing necrotic lysis. Furthermore, α-LA administration led to a significant, dose-dependent restoration of phagolysosome acidification, effectively reversing the maturation blockade imposed by Mtb. Notably, this enhanced acidification inversely correlated with intracellular bacterial survival. These results suggest that α-LA might act as a multifaceted HDT agent capable of restoring both host-protective cell death and phagosomal microbicidal mechanisms. Given its established safety profile and its ability to complement standard anti-TB drugs like Bedaquiline (BDQ), α-LA represents a highly promising candidate for adjunct therapy to improve TB treatment outcomes and mitigate the impact of antibiotic resistance. Full article