Search Results (159)

A series of INH–pyrazole molecular hybrids (6a–o) was synthesized and evaluated for in vitro anti-tubercular activity against drug-susceptible, multidrug-resistant (MDR), and extensively drug-resistant (XDR) Mycobacterium tuberculosis strains, alongside their corresponding precursors (4a–o), using isoniazid (INH) as the reference drug. Overall, the hybrid compounds exhibited inhibitory activity comparable to or exceeding that of INH against the drug-susceptible strain. Among the series, compounds 6a, 6d–6f, and 6m demonstrated the highest potency, with a minimum inhibitory concentration (MIC) of 0.9 µM, corresponding to an approximately 4.3-fold enhancement relative to INH. Compounds 6b,c, 6g–i, and 6l,m also showed noticeable activity (MIC = 1.95 µM), representing an approximate twofold improvement over INH and significantly outperforming their respective precursors. Notably, compound 6o exhibited enhanced activity against the XDR strain (MIC = 121 µM), reflecting an approximately 2.8-fold improvement compared to precursor 4o (MIC > 341 µM), thereby highlighting the advantage of molecular hybridization. However, all compounds displayed diminished activity relative to INH against the resistant strains. Against the MDR strain, compounds 4h, 6e, and 6g displayed measurable activity, with MIC values of 76, 125, and 112 µM, respectively. Cytotoxicity assessment using THP-1 human monocytic cells revealed low toxicity, with all tested compounds maintaining acceptable cell viability at 10 µg/mL. In addition, in silico ADME analysis indicated that the hybrid molecules comply with key drug-likeness criteria. Collectively, these findings suggest that INH–pyrazole hybrids represent promising lead scaffolds for the development of next-generation anti-tubercular agents. Full article

Background: The global burden of drug-resistant Mycobacterium tuberculosis continues to threaten tuberculosis control efforts, largely due to the emergence and transmission of resistance-associated genetic mutations. Molecular epidemiology provides critical insights into mutation profiles and resistance associations, yet the interplay among key mutations and their contributions to complex resistance patterns remains poorly understood, particularly in high-burden settings. Methods: A retrospective, cross-sectional, laboratory-based design was used to analyze 111 phenotypically confirmed drug-resistant isolates. Molecular drug susceptibility testing (DST) for first- and second-line anti-tuberculosis drugs was performed at the National Health Laboratory Service (NHLS) TB reference laboratory. Drug-resistance profiles were classified according to World Health Organization (WHO) definitions. Descriptive and inferential statistical analyses were conducted to determine mutation frequencies, co-occurrence patterns, and associations with resistance profiles. Results: rpoB (D435V 38.7%; S450L 36.0%) and katG (S315T 80.2%) mutations predominated, forming the core molecular basis of MDR-TB, while 15% harbored inhA promoter mutations associated with low-level isoniazid resistance. The most frequent combinations included rpoB S450L with katG S315T and rpoB D435V with katG S315T, consistent with multidrug-resistant tuberculosis (MDR-TB) profiles. Nearly 48% showed dual resistance to fluoroquinolones and second-line injectables. Conclusion: This study highlights the predominance of resistance-associated mutations and their co-occurrence patterns in shaping MDR-TB profiles in the study setting. The observed burden of second-line drug resistance underscores the importance of comprehensive resistance testing. These findings support the use of mutation profiling for rapid diagnosis and informed treatment decisions, while emphasizing the need for ongoing local surveillance to guide TB control efforts. Full article

Background: Drug-resistant tuberculosis (DR-TB) remains a major public health challenge in South Africa, particularly in rural settings with high HIV co-infection rates. Understanding predictors of treatment response among people living with HIV is essential for improving clinical management and programmatic outcomes. This study aimed to identify socio-demographic and clinical predictors of treatment outcomes among HIV-positive individuals diagnosed with multidrug-resistant (MDR) and extensively drug-resistant tuberculosis (XDR-TB) in rural Eastern Cape Province, South Africa. Methods: A retrospective cohort study was conducted using routinely collected clinical records of DR-TB patients initiated on treatment between January 2020 and December 2024 at two public healthcare facilities. A total of 239 patients with complete treatment outcome data were included. Treatment outcomes were classified as favourable (cured or treatment completed) or unfavourable (death, treatment failure, or loss to follow-up). Descriptive statistics were used to summarise patient characteristics, while univariate and multivariable logistic regression analyses were performed to identify factors associated with treatment outcomes. Results: Most participants were aged ≤ 39 years (58%), male (60%), unemployed (90%), and without income (80%). MDR-TB accounted for 40% of cases, rifampicin-resistant-TB (RR-TB) for 53%, and XDR-TB for 7.1%. Multivariable analysis showed that XDR-TB was the strongest independent predictor of unfavourable treatment outcome (AOR = 0.18; 95% CI: 0.06–0.58; p = 0.004). Income status was also significantly associated with outcome, with participants reporting some incomes having lower odds of favourable outcomes (AOR = 0.46; 95% CI: 0.23–0.92; p = 0.036). The model demonstrated modest predictive performance (AUC = 0.67). Conclusions: These findings highlight the dominant influence of resistance phenotype, particularly XDR-TB, on treatment prognosis among HIV-positive DR-TB patients in rural Eastern Cape. Integrating early resistance profiling, intensified clinical management of XDR-TB, and socioeconomic support mechanisms may improve treatment outcomes in high-burden rural settings. Full article

Drug-resistant tuberculosis (DR-TB) represents a major public health threat, particularly in the prisons of Latin America and the Caribbean, where rates are up to 40 times higher than those observed in the general population. These facilities act as community amplifiers due to overcrowding, poor ventilation, diagnostic delays, and treatment discontinuity. This study offers a critical reflection on the magnitude, determinants, and implications of DR-TB in regional penitentiary contexts. A reflective analytical review was conducted in PubMed, Scopus, Web of Science, SciELO, and LILACS, complemented by WHO and PAHO reports, prioritising studies from 2019 to 2024. The findings reveal MDR-TB and pre-extensively drug-resistant (pre-XDR) outbreaks in Peru, Paraguay, and the Dominican Republic, as well as community transmission linked to prisons in Brazil and Colombia. Persistent gaps remain in systematic screening, drug susceptibility testing coverage, and post-release follow-up. Scientific production continues to be uneven and predominantly biomedical, with limited consideration of social and human rights determinants. DR-TB in prisons reflects the structural deficiencies of health and justice systems; its control requires intersectoral policies, genomic surveillance, and strategies that ensure early diagnosis, treatment continuity, and dignified detention conditions. Full article

Background: Antimicrobial resistance is a threat that increases morbidity and mortality. This cross-sectional study aimed to describe the profile of priority antimicrobial-resistant pathogens and to analyze the behavior of multidrug-resistant tuberculosis (MDR-TB) in the Santiago de Cali District, Colombia. Methods: researchers compiled information from data provided by healthcare institutions, the National Public Health Surveillance System, and laboratory-based surveillance using the World Health Organization’s WHONET v.5.6 software. Univariate statistical analysis described trends in pathogen resistance, and multivariate analysis analyzed the behavior of MDR-TB. Results: Among Gram-negative bacteria, high levels of carbapenem resistance were observed in A. baumannii (84% aztreonam resistance) and in K. pneumoniae (63%). P. aeruginosa exhibited elevated multidrug resistance, consistent with extensive antimicrobial selective pressure. MDR-TB exhibited a high burden of resistance, reaching 96%, with projections indicating a potential increase driven by monoresistance and resistance to rifampicin. Patients with drug-resistant tuberculosis who were HIV-positive or experiencing homelessness had a significantly higher likelihood of hospitalization (OR 5.59; 95% CI 3.09–10.11 and OR 2.94; 95% CI 1.48–5.81, respectively) and mortality (OR 3.34; 95% CI 1.72–6.49 and OR 2.59; 95% CI 1.16–5.79, respectively). Conclusions: The expansion of resistance mechanisms suggests sustained selective pressure, underscoring the need for strategies to optimize antibiotics. Full article

Rapid and accurate detection of drug-resistant tuberculosis (DR-TB) is critical for effective treatment and containment. The Xpert^® MTB/XDR (GXXDR) assay is designed to detect Mycobacterium tuberculosis complex (MTBC) and resistance to isoniazid and second-line anti-TB drugs directly from clinical specimens. We evaluated the clinical performance of GXXDR using 61 MTBC-positive specimens with available phenotypic drug susceptibility testing results. GXXDR results were compared to a phenotypic drug susceptibility test (pDST) and whole-genome sequencing (WGS) to assess sensitivity, specificity, and concordance. Resistance to isoniazid, fluoroquinolones, amikacin, capreomycin, and ethionamide was analyzed. Sensitivity comparisons between GXXDR, WGS, pDST, and manufacturer data were performed using Fisher’s exact and Tango tests. GXXDR demonstrated a high specificity for most drugs and a strong sensitivity for isoniazid (93.8%) and fluoroquinolone (92.3%), consistent with manufacturer reports. In contrast, the sensitivity for amikacin (58.3%), capreomycin (35.7%), and ethionamide (27.3%) was significantly lower than stated by the manufacturer (91.9%, 84.0% and 64.7%, respectively), likely due to resistance mutations outside the assay’s target regions. Sensitivity concordance of GXXDR with WGS was high for all drugs, except ethionamide. The GXXDR assay enables rapid and reliable detection of isoniazid and fluoroquinolone resistance in clinical settings, though sensitivity for certain second-line drugs may be affected by regional genetic diversity. These findings underscore the importance of integrating local epidemiological data to optimize molecular diagnostics for DR-TB. Full article

In the last three decades, 2-oxazolidinones have emerged as an important class of inhibitors of bacterial protein synthesis, effective in the treatment of multidrug-resistant (MDR) bacterial infections. From a public health perspective, the importance of 2-oxazolidinones is related to the treatment of tuberculosis (TB), primarily MDR-TB and extensively drug-resistant XDR-TB. Linezolid, the first oxazolidinone antibiotic approved by FDA, is still used in therapy despite common adverse events, such as myelosuppression and serotonergic toxicity, as well as the increasing percentage of linezolid-resistant bacteria (Staphylococcus aureus, enterococci and methicillin-resistant S. aureus). Tedizolid phosphate was the second commercially available oxazolidinone antibiotic approved, followed by other oxazolidinones (contezolid, radezolid, ranbezolid, sutezolid, delpazolid, cadazolid, TBI-233 and MK-7762) that are in clinical study. Contezolid is approved in China and cadazolid has entered phase III clinical trials. This comprehensive review intends to provide an overview of the compounds belonging to this class already in use in therapy and/or clinical studies and to portray the most significant and recent outcomes regarding new oxazolidinones under study. Three literature databases, i.e., PubMed/MEDLINE, Google Scholar and Scopus, were used for the literature search, particularly focusing on the last five years, and screened using different keywords. The design of new drugs belonging to this class may be of considerable interest to researchers and clinicians, contributing to the discovery of new antibiotics that retain antibacterial activity but have fewer side effects. Full article

Background: To effectively manage tuberculosis (TB), it is essential to address the high incidence of the disease, as multidrug-resistant pulmonary TB (MDR-PTB) remains a significant concern to halt pre-extensive drug-resistant (pre-XDR) recrudescence. The objective of the current study was to examine and compare MDR-PTB patterns among adult PTB patients (>12 years) in Bangladesh’s urban and rural areas who had newly diagnosed and previously treated PTB. Methods: A total of 430 newly diagnosed and previously treated adult patients with PTB were randomly recruited during two study periods: the 1st period, from May 2010 to December 2010 (eight months), and the 2nd period, from January 2014 to January 2015 (thirteen months). Only the drug-resistant (DR) patients were included in the final analysis. Mycobacteriological tests, i.e., smear microscopy, culture, drug susceptibility testing (proportion method of Canetti), line-probe assay, and GeneXpert MTB/RIF were performed. Logistic regression analysis was used to determine the strength of associations between treatment outcomes and predictor variables. Results: Of the newly diagnosed patients, 156 cases were negative and drug-sensitive (DS) at diagnosis, and 274 patients exhibited various DR patterns. During the 1st period, MDR-PTB was 26% among newly diagnosed patients, while the proportion was 31% among previously treated patients in the 2nd period. The majority of MDR-PTB belonged to the age group of ≤45 years. Male patients consistently revealed a higher proportion of MDR-PTB compared to females in both the newly diagnosed and previously treated groups. Conclusion: The proportion of MDR-PTB was higher among the previously treated patients than among newly diagnosed patients. Regardless of demographic characteristics, a significant proportion of patients showed DR, particularly in previously treated groups, indicating a substantial burden of MDR-PTB. Full article

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a global health burden, particularly due to multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. Rifampicin, a frontline anti-TB drug that inhibits RNA polymerase, has been central to therapy, but rpoB mutations compromise its efficacy. This highlights the need for Rifampicin analogues that target alternative enzymes to sustain therapeutic effectiveness. In this study, a structure-based computational approach was employed to screen Rifampicin analogues against enoylacyl carrier protein reductase (InhA), a validated enzyme in the biosynthesis of mycolic acids. A library of 399 analogues was retrieved from SwissSimilarity and evaluated using ADMET analysis, with the best candidates showing favourable pharmacokinetic profiles and compliance with Lipinski’s Rule of Five. Molecular docking identified ZINC000013629834 (−10.90 kcal/mol) and ZINC000253411694 (−10.36 kcal/mol) as superior to Rifampicin (−9.05 kcal/mol), with ILE21, SER20, and THR196 consistently stabilizing interactions. Molecular dynamics simulations confirmed the stability of the complexes, with RMSD values of 0.167 nm, 0.175 nm, and 0.297 nm for ZINC000013629834, ZINC000253411694, and Rifampicin, respectively. MM/PBSA analysis showed comparable binding free energies. These findings suggest that optimized Rifampicin analogues targeting InhA may overcome rpoB-associated resistance and serve as promising leads for next-generation anti-TB drug development. Full article

Tuberculosis, caused by Mycobacterium tuberculosis (M. tb), remains a leading global threat, escalated now by the rise of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains. In search of a novel anti-tubercular agent with a distinct mechanism of action, this study explores deep-sea marine metabolites as potential inhibitors of the F₄₂₀-dependent oxidoreductase Rv1155, a redox enzyme essential for M. tb survival. A total of 2773 marine-derived compounds curated from the CMNPD, Reaxys, and MarinLit databases were screened using an integrated CADD workflow combining molecular docking, in-silico ADMET profiling, and molecular dynamics (MD) simulations. Docking identified 68 metabolites with strong affinity (−10.98 to −15.95 kcal/mol) for the Rv1155 binding pocket, and from which three compounds, Upenamide (CMNPD_22964), Aspyronol (Compound_1749), and Fiscpropionate F (Compound_1796), were shortlisted as hit candidates. Among these, Upenamide displayed the strongest binding (ΔG = −28.56 kcal/mol) with stable RMSD and hydrogen bond persistence during 100 ns MD simulation, while Aspyronol demonstrated a promising ADMET profile comparable to the native cofactor F₄₂₀₂. MM-GBSA analysis further confirmed the strong binding strength (ΔG _bind = −24.77 to −34.07 kcal/mol) for all three hit candidates. These findings confirm the strong and stable interaction of selected deep-sea marine metabolites with Rv1155. This validated screening pipeline established here provides a cost-effective framework for future experimental validation and expansion to additional F₄₂₀-related drug targets in M. tb. Full article

National Tuberculosis Reference Laboratories (NTRLs) are central to tuberculosis (TB) control programs. Between 2018 and 2024, the Republic of Congo, a country of 6 million inhabitants, achieved a transformative strengthening of its TB diagnostic system, coordinated by the NTRL. Strategic investments, supported mainly by international partners, enabled a substantial decentralization of services, expanding the diagnostic network from 38 to 113 diagnostic and testing centers and increasing GeneXpert sites from 3 to 31. The expansion of the diagnostic network and specimen referral system was associated with a reduced structural gap in diagnostic coverage by extending access to GeneXpert testing to a larger number of peripheral and previously underserved centers. Critically, the establishment of a BSL-3 laboratory and the deployment of advanced assays like Xpert MTB/XDR ended the reliance on overseas testing by introducing in-country capacity for multidrug-resistant and pre-extensively drug-resistant TB detection. These systemic improvements were associated with significant positive outcomes, including an annual molecular testing surging from 11,609 in 2022 to over 27,000 in 2024 and bacteriological confirmation rates rising from 34 to 73%. This comprehensive laboratory systems strengthening, which also facilitated cross-programmatic initiatives like HIV and Mpox testing integration, underscores how sustained investment in infrastructure, logistics, and quality management is fundamental to improving case detection, surveillance, and progress toward the WHO End TB Strategy milestones. Full article

Tuberculosis (TB) remains a leading infectious killer, increasingly complicated by multidrug-resistant (MDR) and extensively drug-resistant (XDR) disease; current regimens, although effective, are prolonged, toxic, and often fail to reach intracellular bacilli in heterogeneous lung lesions. This narrative review synthesizes how next-generation antimycobacterial strategies can be translated “from molecule to patient” by coupling potent therapeutics with delivery platforms tailored to the lesion microenvironment. We survey emerging small-molecule classes, including decaprenylphosphoryl-β-D-ribose 2′-epimerase (DprE1) inhibitors, mycobacterial membrane protein large 3 (MmpL3) inhibitors, and respiratory chain blockers, alongside optimized uses of established agents and host-directed therapies (HDTs). These are mapped to inhalable and nanocarrier systems that improve intralesional exposure, macrophage uptake, and targeted release while reducing systemic toxicity. Particular emphasis is placed on pulmonary dry powder inhalers (DPIs) and aerosols for direct lung targeting, stimuli-responsive carriers that trigger release through pH, redox, or enzymatic cues, and long-acting depots or implants that shift daily dosing to monthly or quarterly schedules to enhance adherence, safety, and access. We also outline translational enablers, including model-informed pharmacokinetic/pharmacodynamic (PK/PD) integration, device formulation co-design, manufacturability, regulatory quality frameworks, and patient-centered implementation. Overall, aligning stronger drugs with smart delivery platforms offers a practical pathway to shorter, safer, and more easily completed TB therapy, improving both individual outcomes and public health impact. Full article

Background: The global incidence of multidrug-resistant and extensively drug-resistant tuberculosis continues to rise. The ribosome serves as a target for multiple antimicrobials, making functional research on it hold great significance. Methods: Using homologous recombination combined with a multiple serine integrase-mediated site-specific recombination system, we replaced the two endogenous rRNA operons in Mycobacterium smegmatis MC² 155 with a single copy of the single rRNA operon from Mycobacterium tuberculosis H37Rv, constructing the M. smegmatis BRkoA strain. We assessed growth kinetics at 37 °C, cold sensitivity at lower temperatures, transcriptional levels by RT-qPCR, 70S ribosome integrity through cryo-EM, and antimicrobial susceptibility by microdilution assays. Results: The BRkoA strain was successfully constructed. It exhibited markedly slower growth compared to the wild-type strain. Cold-sensitivity assays indicated potential ribosome assembly defects, while transcriptional analysis suggested altered rRNA processing and modification. Cryo-EM analysis further demonstrated the absence of specific ribosomal proteins in the BRkoA 70S ribosome. Moreover, BRkoA displayed reduced susceptibility tendency to several ribosome-targeting antibiotics, including kanamycin, amikacin, paromomycin, gentamicin, and linezolid. Conclusions: Replacement of the two endogenous rrn operons in M. smegmatis with a single copy of the single M. tuberculosis rrn operon using a serine integrase-mediated recombination system caused growth impairment and decreased sensitivity tendency to several ribosome-targeting antimicrobials. These findings suggest that ribosome structural variation contributes to intrinsic drug resistance mechanisms. Full article

Background: Tuberculosis (TB) remains a critical global health concern, exacerbated by the emergence of multidrug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis. In the search for novel therapeutic agents, naphthoquinones have garnered interest due to their diverse mechanisms of action and potent antimycobacterial activity. In this study, we report the design, synthesis, and biological evaluation of a novel series of eleven naphthoquinone-based derivatives (compounds 22–32), developed through a molecular hybridization strategy targeting shikimate kinase (Mtb-SK) an essential enzyme present exclusively in M. tuberculosis. Methods: The compounds were synthesized via a straightforward and efficient synthetic route, and preliminary screening identified five molecules with significant anti-TB activity. Notably, compound 26, 4-(4-ethoxyphenyl) amino) Naphthalene-1,2-dione, exhibited a minimum inhibitory concentration (MIC) of 21.33 µM, comparable to ethambutol and substantially more potent than pyrazinamide. Results: Molecular docking studies indicated that all active compounds interact favorably within the shikimate binding pocket of Mtb-SK, following the proposed mechanism of action. Additionally, ongoing cytotoxicity assays in HepG2 cells aim to assess the selectivity of these derivatives. Conclusions: These findings support the potential of this new class of naphthoquinones as promising scaffolds for the development of anti-TB agents, contributing to the growing body of research focused on new chemotherapeutic options against tuberculosis. Full article

Tuberculosis (TB), caused by Mycobacterium tuberculosis, continues to be a leading cause of morbidity and mortality in Mexico, with more than 20,000 new cases annually and a rising proportion of drug-resistant strains. This work addresses the molecular epidemiology of TB in the Mexican context, emphasizing its role in understanding transmission, genetic diversity, and resistance mechanisms. To achieve this, we reviewed molecular typing approaches including spoligotyping, Mycobacterial Interspersed Repetitive Unit–Variable Number Tandem Repeat (MIRU-VNTR) analysis, and whole-genome sequencing (WGS), which have been applied to characterize circulating lineages and identify drug-resistance-associated mutations. The results indicate that the Euro-American lineage (L4) predominates across the country, although significant regional variation exists, with Haarlem, LAM, T, and X sub lineages dominating in different states, and occasional detection of Asian (L2) and Indo-Oceanic (L1) lineages. Key resistance mutations were identified in katG, rpoB, pncA, and gyrA, contributing to the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains, particularly in border and marginalized regions. These findings highlight how social factors, such as migration, urban overcrowding, and comorbidities including diabetes and HIV, influence transmission dynamics. We conclude that integrating molecular tools with epidemiological surveillance is crucial for strengthening public health strategies and guiding interventions tailored to Mexico’s heterogeneous TB burden. Full article