Search Results (277)

Background: Multidrug-resistant tuberculosis (MDR-TB) remains a significant public health threat in Central Asia, where rising resistance to first-line anti-TB drugs challenges control efforts. As of 2024, the World Health Organization (WHO) reports that over 2.5% of new TB cases and 18% of previously treated cases are resistant to first-line TB drugs worldwide. Objectives: This integrative review synthesizes current evidence on MDR-TB in Kazakhstan, Kyrgyzstan, Tajikistan, Turkmenistan, and Uzbekistan, with a focus on infection control, diagnostic advancements, and evolving treatment strategies. Methods: A comprehensive literature search was conducted across five electronic databases: PubMed, Scopus, Web of Science, Embase, World Health Organization (WHO) Global Tuberculosis Database, and ClinicalTrials.gov. A total of 29 articles from Central Asian countries met the inclusion criteria. Results: Four main themes were identified: “genetic variability and resistance patterns of MDR-TB strains”; “barriers to effective treatment”; “diagnostic tools”, and “infection control strategies”. Conclusions: This review underscores the importance of comprehensive, multifactorial approaches in addressing drug-resistant TB in the region. The implementation of early diagnosis and all-oral treatment regimens has improved adherence in recent studies. Full article

The global burden of tuberculosis (TB), exacerbated by the rise of drug-resistant Mycobacterium tuberculosis (M. tuberculosis), underscores the need for alternative intervention strategies. One promising approach is to block the infection at its earliest stage—bacterial adhesion to host cells—thereby preventing colonization and transmission without exerting selective pressure. Adhesins, surface-exposed molecules mediating this critical interaction, have therefore emerged as attractive targets for early prevention. This review outlines the infection process driven by bacterial adhesion and describes the architecture of the M. tuberculosis outer envelope, emphasizing components that contribute to host interaction. We comprehensively summarize both non-protein and protein adhesins, detailing their host receptors, biological roles, and experimental evidence. Recent progress in the computational prediction of adhesins, particularly neural network-based tools like SPAAN, is also discussed, highlighting its potential to accelerate adhesin discovery. Additionally, we present a detailed, generalized workflow for predicting M. tuberculosis adhesins, which synthesizes current approaches and provides a comprehensive framework for future studies. Targeting bacterial adhesion presents a therapeutic strategy that interferes with the early stages of infection while minimizing the risk of developing drug resistance. Consequently, anti-adhesion strategies may serve as valuable complements to conventional therapies and support the development of next-generation TB vaccines and treatments. Full article

(1) Background: The occurrence, intensity, and characteristics of adverse drug reactions (ADRs) caused by anti-tuberculosis (TB) drugs have consistently been a subject of worry. There is a lack of published research from Pakistan regarding the negative effects of anti-TB treatment on children, specifically about ADRs. In this study, we aimed to investigate the ADR associated with anti-DR-TB treatment in children. (2) Methods: A prospective longitudinal study was conducted in the multicenter setting of Khyber Pakhtunkhwa, Pakistan. A total of 450 TB children in multicenter hospitals under ATT were assessed for ADRs. Naranjo Causality Assessment and Hartwig’s Severity Assessment Scale were used to evaluate the causality and severity. (3) Results: A total of 300 (66.66%) ADRs were reported in 450 people with DRTB. Anemia was the most frequently observed ADR (37.6%) followed by nausea and vomiting (18.6%). On multivariate analysis, the independent variables that had a statistically significant positive association with ADRs were participants aged, 5–14 years (AOR, 0.3 (0.1–0.5), p ≤ 0.001), normal weight (1.1 (2.0–1.9), p < 0.001), and children having comorbidities (AOR, 0.5 (0.1–0.8), p ≤ 0.001). (4) Conclusions: Our findings advocate for personalized treatment approaches, incorporating nutritional support, comprehensive comorbidity management, and vigilant monitoring to mitigate ADRs and improve treatment outcomes. Full article

Objectives: To investigate epidemiological/drug-resistance characteristics and identify potential factors related to drug-resistant and clustered tuberculosis in Sichuan. Methods: A total of 295 Mycobacterium tuberculosis (MTB) isolates were collected from surveillance sites in Sichuan from 2019 to 2021. The minimum inhibitory concentrations (MICs) of 12 anti-TB drugs were acquired using the broth microdilution method, followed by whole-genome sequencing (WGS) analysis. Results: Of 268 MTB isolates with both WGS and drug-susceptibility testing (DST) results, 159 (59.3%, 159/268) strains belonged to the Beijing lineage (L2). Isoniazid had the highest resistance rate (15.3%, 41/268), followed by rifampicin (9.3%, 25/268). The sensitivity of WGS to predict drug resistance varied from 75% to 97.6%, and the specificity was above 96.0% for all. rpoB Ser450Leu (41.7%, 10/24) and katG Ser315Thr (70%, 28/40) were the most frequent mutations in rifampicin and isoniazid resistance isolates, respectively. The clustering rate in Sichuan was 9.3% (25/268), and patients ≤ 24 years old (aOR = 11.697; 95% CI: 0.817–167.463) had a greater risk of clustering. Conclusions: Our findings prove that WGS is a promising tool for predicting drug resistance to isoniazid, rifampicin, ethambutol, moxifloxacin and levofloxacin in Sichuan. The higher resistance rate to isoniazid emphasizes the urgent need for susceptibility testing surveillance and application management. Improving the diagnosis, treatment and management of patients ≤ 24 years old may reduce the transmission of MTB in Sichuan. Full article

Worldwide, several million people are infected with mycobacteria such as Mycobacterium tuberculosis (M. tb) or non-tuberculous mycobacteria (NTM). In 2023, 10.8 million cases and 1.25 million deaths due to M. tb were recorded. In Europe and North America, the emergence of NTM is tending to outstrip that of M. tb. Among pulmonary NTM, Mycobacterium avium complex (MAC) is the most common, accounting for 80% of NTM infections. First-line treatment requires the combination of at least three antibiotics over a long period and with different mechanisms of action to limit cross-resistance. The challenge is to discover more effective new anti-MAC molecules to reduce the duration of treatment and to overcome resistant strains. The aim of this review is to present an overview of the challenges posed by MAC infection such as side effects, reinfections and resistance mechanisms. The latest therapeutic options such as the optimized combination therapy, drug repurposing and the development of new formulations, as well as new anti-MAC compounds currently in (pre)clinical trials will also be discussed. Full article

Background and Objectives: Tuberculosis (TB) is one of the most common infectious diseases in developing countries. The resistance of the causative agent, Mycobacterium tuberculosis, to two or more first-line anti-TB drugs results in multidrug-resistant (MDR) TB, posing a serious challenge to the control of TB worldwide. This study was designed to determine the changes in drug resistance over time in TB strains isolated from patients in all departments of Uludağ University Hospital in western Türkiye. Materials and Methods: We retrospectively analyzed 104,598 clinical samples sent to our laboratory for the investigation of the presence of TB between 1996 and 2023. BACTEC 460 TB, BACTEC MGIT 960 culture systems and Löwenstein–Jensen medium were used for the culture of these samples. The susceptibility of M. tuberculosis complex strains grown in culture to isoniazid (INH) (0.1 μg/mL), rifampicin (RIF) (1.0 μg/mL), ethambutol (ETB) (5.0 μg/mL) and streptomycin (SM) (1.0 μg/mL) antibiotics was studied according to the manufacturer’s recommendation. Results: Out of 104,598 patient samples, 2752 (2.6%) were culture-positive, and the susceptibility test results of 1869 of these were analyzed. Of the isolates, 358 (19.2%) were found to be resistant to at least one first-line drug, i.e., INH, RIF, ETB, or SM. In addition, 2.9% were resistant to two or more first-line drugs. Conclusions: Drug susceptibility testing is essential to ensure the optimal treatment and control of drug-resistant TB strains. This study highlights the value of ongoing efforts to control tuberculosis drug resistance in the fight against this disease. Full article

Mycobacterium tuberculosis, the infectious agent behind tuberculosis (TB), underscores the significance of targeting enzymes such as arabinosyltransferases in drug development efforts. Benzothiozinone derivatives, which have been assessed for their effectiveness against TB, present a promising avenue for treatment. Utilizing a high virtual screening quantitative structure–activity relationship (QSAR-VS), a set of forty Benzothiozinone (C1–C40) compounds were investigated to build a robust model with satisfactory performance metrics (R² = 0.82, R²_adj = 0.78, N_test = 10, R²_test = 0.70). This model enabled the creation of databases containing new derivatives for screening drug-like properties and predicting MIC activity in TB treatment. The best-scoring compounds were screened by molecular docking with Mycobacterium tuberculosis kinases A and B (PDB code: 6B2P) and validated by molecular dynamics simulations to elucidate the most stable drug–protein interactions. Additionally, the MM-PBSA analysis shows that the strongest binding occurs in complexes X3, X4, and X6 with ΔG_bind values of −8.2, −15.3, and −12.0 kcal/mol, respectively. Our in silico study aims to prospect these new anti-tubercular drugs and their potential development through perspective in vitro and in vivo assays. Full article

Background/Objectives: In this study, a novel series of 4-(arylchalcogenyl)methyl)-1H-1,2,3-Triazol-1-yl-menadione derivatives were synthesized to explore their potential as new antituberculosis (anti-TB) agents. Selenium-containing compounds are known for their significant antimycobacterial activity, which motivated their inclusion in the design. Methods: The target compounds were synthesized via a copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction, affording yields ranging from 34% to 93%. All compounds were evaluated in vitro for anti-TB activity against Mycobacterium tuberculosis H37Rv (ATCC 27294), as well as a drug-resistant strain (T113/09). Results: Several selenium-containing derivatives exhibited promising activity. Compounds 9b and 9g were equipotent to the first-line anti-TB drug, and one compound surpassed its activity. Notably, compounds 9a, 9b, 9g, and 9h also showed efficacy against the INH- and RIF-resistant Mtb strain T113/09. Conclusions: The efficacy of selenium-containing triazole-menadione hybrids against both sensitive and resistant Mtb strains highlight their potential as candidates for addressing antimicrobial resistance in TB treatment. Further investigations are required to understand their mechanisms of action and assess their in vivo therapeutic potential.. Full article

Background: Pulmonary tuberculosis (TB) frequently leads to long-term lung complications that contribute to increased mortality. Understanding the pathogenesis of post-TB lung impairments is crucial for improving long-term outcomes in TB patients; yet this area remains poorly researched. Methods: Our study assessed circulatory inflammatory markers in patients who completed TB treatment more than one year before enrolment (population 1) and patients receiving in-hospital treatment for active drug-sensitive TB (population 2). Results: IL-6 was seven times higher in both populations compared to the normal range. IL-8 was below the limit of detection (LOD) in population 1, while it was approximately 2.5 times higher in population 2 compared to the normal range. TNF-α was 21 times higher in population 1 and 19 times higher in population 2 compared to the normal range. CRP was almost 49 times higher in both populations, and IL-1Ra was below the LOD in population 1, while it was ~1.5 times higher in population 2 compared to the normal range. Conclusions: These inflammatory biomarkers correlated well with lung function in the post-TB state, and their high levels suggest a persistent pro-inflammatory state post-TB, which may contribute to post-TB lung disease. More research is warranted to better understand this phenomenon, but these findings may highlight a need to consider anti-inflammatory therapy for patients with post-TB lung disease, especially since these high levels of cytokines can directly contribute to lung damage. Full article

Background: The appearance of new clinical manifestations (for example, subcutaneous or skin abscesses) during anti-tuberculosis treatment is generally indicative of therapeutic failure. The cause of therapeutic failure may be the presence of a drug-resistant Mycobacterium infection or to the failure to achieve a sufficient concentration of the drugs in the bloodstream. Case report: Here, we report the case of a 25-year-old man suffering from tuberculosis infection with lymph-node and pulmonary involvement and an atypical response to specific therapy. Two weeks after starting four-drug antitubercular treatment, the patient began to experience fever, pain and functional impotence in the left foot and ankle, with subsequent evidence of ankle and tarsal osteomyelitis. Four weeks after starting treatment, the patient presented with several widespread, painful subcutaneous abscesses on the trunk, back and right lower limb. Drainage was performed from the ankle and from one of the abscesses, and polymerase chain reaction (PCR) showed a positive result for M. tuberculosis in both samples, with the absence of resistance to drugs. Anti-tubercular medications were continued, with resolution of the pulmonary and bone involvement but with persistence of subcutaneous abscesses, although subsequent drainages showed the absence of mycobacterium tuberculosis. Conclusions: We describe an unusual presentation of paradoxical reaction in the form of osteomyelitis and subcutaneous abscesses in an immunocompetent TB patient, and we reported other similar cases of paradoxical reactions described in the literature in the last ten years, which demonstrate the importance of considering paradoxical reactions in patients who present with new or worsening signs and symptoms after starting tuberculosis treatment. Full article

The long regimen of drug therapy, the emergence of drug-resistance (DR), and infections with non-tuberculous mycobacteria (NTMs) are alarming challenges in controlling tuberculosis (TB), a disease caused by Mycobacterium tuberculosis (M.tb), necessitating the pursuit of new, broad-spectrum anti-mycobacterials. With more than two-thirds of the clinically useful antibiotics originating from the bacterial phylum Actinomycetota, and their enormous diversity in India, we explored atypical environments for new bacterial strains with potential anti-M.tb activity. In this study, we the examined the secondary metabolites of soil and endophytic bacterial isolates from the wetland niches of Manipur, India, and determined their anti-mycobacterial properties using viability assays. The ethyl acetate culture filtrate extracts of one of the isolates, named Streptomyces sp. SbAr007, showed broad-spectrum anti-mycobacterial activity against laboratory M.tb strains H37Ra and H37Rv, a clinical drug-resistant M.tb and non-tuberculous mycobacteria (NTM). The isolate was characterized for its phenotype and genetic identity, which indicated its closeness to Streptomyces samsunensis, Streptomyces malaysiensis, and Streptomyces solisilvae. Further, macrophage infection assays showed that the extracts could effectively control the intracellular mycobacterial growth but had negligible cytotoxicity to PBMCs from healthy donors. LC-MS identified an unusual combination of antibiotics in these culture filtrate extracts, which can be further explored for specific active molecules or as a formulation against DR-TB. Full article

Tuberculosis (TB) is a leading cause of death from a single infectious agent in humans. The morbidity and mortality due to TB are further worsened by co-existing health conditions and the emergence of drug-resistant (DR-TB) cases. The WHO has declared TB as a global emergency and endorsed global efforts to improve diagnosis, and treatment while reducing the catastrophic cost in an EndTB strategy in 2013, with a vision to create a TB-free world. In the past decade, molecular diagnostic tools, such as nucleic acid amplification technologies (NAATs), have replaced the conventional smear microscopy of TB, thus offering better bacteriological confirmation and case detection along with drug resistance in pulmonary and extrapulmonary samples. Follow-on testing using a more advanced targeted next-generation sequencing (tNGS) system has improved the diagnosis of cases resistant to first- and second-line anti-TB drugs, including newer ones. TB treatment has been improved with the introduction of newer drugs including an all-oral regimen for DR-TB, thereby improving patient compliance. Improved TB prevention is achieved through the broadening of BCG vaccination as well as preventive therapy for asymptomatic, latent TB (LTBI) cases, which, otherwise, can reactivate to symptomatic disease. However, the recent goal of the WHO’s EndTB-2035 strategy has been met with significant challenges in the areas of implementing improved diagnosis and treatment modalities in resource-limited TB endemic countries. The complexity of global TB management is confounded by malnutrition, comorbidities with other infectious and non-infectious diseases, and the socio-economic landscape of vulnerable populations. Political commitment to universal health coverage (UHC), including service coverage and reduction in catastrophic cost, are some of the essential components that need to be addressed to achieve the EndTB strategy. In this perspective, we have highlighted the intricacies of global TB management and summarized some of the key challenges that may keep the WHO’s EndTB-2035 strategy on the fence. Full article

Tuberculosis (TB) remains a major cause of ill health and one of the leading causes of death worldwide, with about 1.25 million deaths estimated in 2023. Control measures have focused principally on early diagnosis, the treatment of active TB, and vaccination. However, the widespread emergence of anti-tuberculosis drug resistance remains the major public health threat to progress made in global TB care and control. Moreover, the Bacillus Calmette–Guérin (BCG) vaccine, the only licensed vaccine against TB in children, has been in use for over a century, and there have been considerable debates concerning its effectiveness in TB control. A multi-epitope vaccine against TB would be an invaluable tool to attain the Global Plan to End TB 2023–2030 target. A rational approach that combines several B-cell and T-cell epitopes from key lipoproteins was adopted to design a novel multi-epitope vaccine candidate. In addition, interactions with TLR4 were implemented to assess its ability to elicit an innate immune response. The conservation of the selected proteins suggests the possibility of cross-protection in line with the One Health approach to disease control. The vaccine candidate was predicted to be both antigenic and immunogenic, and immune simulation analyses demonstrated its ability to elicit both humoral and cellular immune responses. Protein–protein docking and normal-mode analyses of the vaccine candidate with TLR4 predicted efficient binding and stable interaction. This study provides a promising One Health approach for the design of multi-epitope vaccines against human and livestock tuberculosis. Overall, the designed vaccine candidate demonstrated immunogenicity and safety features that warrant further experimental validation in vitro and in vivo. Full article

Background: Pakistan is classified as a high-burden country for tuberculosis, and the prescription of antibiotics and fluoroquinolones complicates the detection and treatment of the disease. The existing literature primarily relies on knowledge questionnaires and prescription analyses, which focus on healthcare providers’ knowledge rather than their actual clinical practices. Therefore, this study aimed to evaluate the quality of tuberculosis care using standardized patients. Materials and Methods: We conducted a cross-sectional study, recruiting consenting private healthcare practitioners in four cities in Punjab, Pakistan. Standardized patients were engaged from the general public to simulate four cases: two suspected tuberculosis cases (Case 1 and 2), one confirmed tuberculosis case (Case 3), and one suspected multidrug-resistant tuberculosis case (Case 4). The optimal management in Cases 1 and 2 was referral for sputum testing, chest X-ray, or referral to a public facility for directly observed treatment short-courses without dispensing antibiotics, fluoroquinolones, and steroids. In Case 3, treatment with four anti-TB medications was expected, while Case 4 should have prompted a drug-susceptibility test. Descriptive statistics using SPSS version 23 were employed to analyze disparities in referrals, ideal case management, antibiotic use, steroid administration, and the number of medications prescribed. Results: From July 2022 to May 2023, 3321 standardized cases were presented to private healthcare practitioners. Overall, 39.4% of tuberculosis cases were managed optimally, with Case 3 showing the highest rate (56.7%) and Case 4 showing the lowest (19.8%). City-specific analysis revealed that Rawalpindi had the highest management rate (55.8%), while Sialkot had the lowest (30.6%). Antibiotics were most frequently prescribed in Case 1 and least prescribed in Case 4, with a similar pattern for fluoroquinolones. Anti-TB medications were also prescribed in naïve and suspected tuberculosis cases (8.3% in Case 1 and 10.8% in Case 2). Conclusions: The quality of tuberculosis management in actual practice is suboptimal among healthcare providers in Pakistan. Furthermore, the over-prescription of antibiotics, fluoroquinolones, and anti-TB drugs presents a significant risk for the development of drug-resistant tuberculosis. Full article

Background: The increasing prevalence of drug-resistant tuberculosis (TB) underscores the urgent need for novel antimicrobial agents. Methods: This study integrates cultivation optimization, nuclear magnetic resonance (NMR) fingerprinting, and principal component analysis (PCA) to explore microbial secondary metabolites as potential anti-TB agents. Results: Using the combined approach, 11 bioactive compounds were isolated and identified, all exhibiting anti-Mycobacterium bovis BCG activity. Notable findings include borrelidin, a potent threonyl-tRNA synthetase inhibitor with broad biological activities, and L-O-Lac-L-Val-D-O-Hiv-D-Val, a peptide isolated for the first time from a plant endophyte, demonstrating broad-spectrum antimicrobial activity. Additionally, elaiophylin and polycyclic tetramate macrolactams (PTMs) displayed significant bactericidal effects, with elaiophylin achieving complete BCG inhibition at 72 h and PTMs marking their first reported anti-TB activity. The study also identified bafilomycins as potent scaffolds for anti-TB drug development, showcasing rapid bactericidal activity at low MIC values. Conclusions: These findings emphasize the value of microbial metabolites as a reservoir of bioactive compounds and provide new avenues for developing next-generation anti-TB therapies. Full article