Search Results (516)

The incidence of tuberculosis disease (TBD) in New Brunswick (NB) is low but has been rising over the past decade. Analyzing these trends can help identify specific risk factors and transmission patterns to guide targeted public health strategies. This study aimed to provide a comprehensive and detailed characterization of TBD in NB by examining data from 1 January 2002, to 31 December 2024. All TB patients with Mycobacterium tuberculosis complex (MTBC) clinical isolates identified in NB healthcare facilities were eligible for inclusion in the study. We analyzed demographic, drug susceptibility, and 24-locus Mycobacterial Interspersed Repetitive Unit-Variable Number Tandem Repeat (MIRU-VNTR) data from 166 patients. Most MTBC isolates were pan-susceptible to first-line anti-tuberculosis drugs (90.9–98.1%), with 2.4% showing multidrug resistance. The MIRU-VNTR demonstrated a high discriminatory power of 0.9982 and a low clustering rate of 20.4%. Two samples from the same patient, collected seven years apart, showed different genetic profiles, suggesting that the second episode was a new infection. The most prevalent MTBC lineage was East African Indian (n = 23, 13%). This study provides early insights into TB trends in NB, including what may be the first recorded case of TB reinfection in NB. Our findings will help guide future TB research, policies, and public health interventions in the region. Full article

Background/Objectives: Fever and pain are among the most common symptoms in pediatric infections and chronic diseases, causing significant discomfort for children and concern for caregivers. Effective management is essential to relieve distress while avoiding overtreatment or undertreatment. Paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs), particularly ibuprofen, are the primary antipyretic and analgesic agents in pediatric care, but their use in children with chronic conditions might be challenging. Methods: A narrative review and clinical expert judgment were used to synthesize current evidence on the use of paracetamol and NSAIDs (especially ibuprofen) in children with some common chronic diseases. Results: Paracetamol is often considered a first-line option in several chronic conditions. Caution is warranted in children with pre-existing malnutrition, obesity, and neuromuscular disorders as these factors might increase the risk of hepatotoxicity. NSAIDs provide additional anti-inflammatory effects and comparable analgesic efficacy but should be used cautiously in some high-risk populations due to potential gastrointestinal, renal, and bleeding complications. Their use is contraindicated in children with dehydration, renal impairment, nephrotic syndrome relapses, while careful risk-benefit assessment is required in small and vulnerable neonates. Some data also suggests NSAIDs may worsen outcomes in certain acute bacterial and viral infections. Data on chronic infections such as tuberculosis, HIV, and viral hepatitis are limited, highlighting the need for further research. Combination therapy with paracetamol and ibuprofen may enhance analgesia in postoperative settings without significantly increasing adverse events. Overall, available evidence is limited and largely observational. Conclusions: This narrative review synthesizes current evidence and clinical expertise to provide practical guidance on the rational use of paracetamol and NSAIDs in children, emphasizing individualized therapy according to comorbidities, risk factors, and clinical context, particularly in vulnerable populations. A risk-adapted, evidence-based approach ensures optimal symptom control while minimizing harm, supporting safer, more effective, and family-centered care for children with fever and pain. Full article

Mycolic acids (MAs) are unique and essential components of the Mycobacterium cell envelope, pivotal for its structural integrity, impermeability, and intrinsic antibiotic resistance. These properties that underpin mycobacterial pathogenicity also render the MA biosynthetic pathway a rich resource of targets for anti-tuberculosis drug discovery. Concurrently, in the realm of industrial biotechnology, engineered non-pathogenic mycobacteria are being optimized for steroid drug bioproduction through strategic modulation of the MA pathway to enhance cell permeability and boost the yield of desired products. This review systematically delineates the MA biosynthetic pathway and its critical enzymes. It further summarizes recent progress in developing anti-tuberculosis therapeutics that inhibit these enzymes and discusses innovative engineering strategies that harness the same pathway of non-pathogenic mycobacteria for green steroid drug manufacturing. By bridging these two distinct fields, the review provides a holistic perspective and novel insights for advancing both infectious disease control and sustainable pharmaceutical production. 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 is a serious public health issue. It is the most prevalent cause of death from a single infectious agent and globally, it is among the top 10 causes. One of the most crucial strategies to combat the TB pandemic is to administer basic anti-TB treatment for at least six months. However, the long duration of TB therapy raised the issue of non-adherence, which negatively impacted the clinical and public health outcomes of TB treatment. As a result, directly observed therapy has been used as a standard method to encourage adherence to anti-TB medication. However, this strategy has been challenged because of the difficulty, stigma, decreased economic output, and decreased quality of life, all of which might eventually make adherence problems worse. Furthermore, there is disagreement regarding the efficacy of the directly observed treatment (DOT) strategy in enhancing anti-TB adherence. Digital technology might therefore be a key tool to enhance DOT implementation. The World Health Organization Multidimensional Adherence Model (WHO-MAM) may be used with digital technologies to further improve drug adherence and change behavior. Aim: This paper aimed at reviewing the latest evidence on TB drug non-adherence, its contributing factors, the efficacy of DOT and its alternatives, and the use of digital technologies and WHO-MAM to improve medication adherence. This report analyzed linked publications using a narrative review process to address the study goals. Conventional DOT has several drawbacks when it comes to TB therapy. Medication adherence may be enhanced by incorporating WHO-MAM into the creation of digital technologies. To address several challenges associated with DOT implementation, digital technology offers a chance to enhance drug adherence. Full article

Toxin–antitoxin (TA) modules represent sophisticated regulatory networks that have evolved from simple plasmid maintenance factors into multifunctional genetic modules orchestrating bacterial stress responses, pathogenesis, and ecological adaptation. This review highlights a compelling correlation between the abundance of toxin–antitoxin (TA) modules and bacterial pathogenicity, as exemplified by Mycobacterium tuberculosis (M.tb), which encodes 118 TA loci—significantly more than the fewer than 10 found in closely related saprophytic species. The clinical significance of TA modules extends beyond traditional stress response roles to encompass antimicrobial persistence, where systems like VapBC and MazEF facilitate dormant subpopulations that survive antibiotic therapy while maintaining chronic infections. Recent discoveries have revealed TA modules as sophisticated bacterial defense mechanisms against bacteriophage infection, with DarTG and ToxIN systems representing novel antiviral immunity components that complement CRISPR-Cas and restriction–modification systems. The immunomodulatory capacity of TA modules demonstrates their role in host–pathogen interactions, where systems such as VapC12 in M.tb promote macrophage polarization toward permissive M2 phenotypes while inducing anti-inflammatory cytokine production. Large-scale genomic analyses reveal that TA modules function as drivers of horizontal gene transfer networks, with their signatures enabling accurate prediction of plasmid community membership and serving as determinants of microbial community structure. The biotechnological applications of TA modules have expanded to include genetic circuit stabilization, biocontainment device construction, and multi-species microbial community engineering, while therapeutic strategies focus on developing multi-target inhibitors against conserved TA protein families as promising approaches for combating drug-resistant bacterial infections. The evolutionary conservation of TA modules across diverse bacterial lineages underscores their fundamental importance as central organizing principles in bacterial adaptation strategies, where their multifunctional nature reflects complex selective pressures operating across environmental niches and host-associated ecosystems. This review provides an integrated perspective on TA modules as dynamic regulatory elements that support bacterial persistence, immune evasion, and ecological versatility, establishing them as genetic elements with truly “many faces and functions” in prokaryotic biology. Full article

Background: Tuberculosis (TB) remains a leading cause of global mortality, with 1.25 million deaths reported in 2023. Extended treatment duration contributes to poor patient adherence and treatment failure. Innovative drug delivery platforms are needed to improve therapeutic outcomes. Objective: This study aimed to develop nanoemulsions co-encapsulating quercetin and rifampicin and evaluate their physicochemical properties and in vitro biological activity relevant to TB therapy. Methods: Nanoemulsions (NEs) were prepared via hot solvent diffusion and phase inversion temperature techniques. Physicochemical characterization, stability, anti-inflammatory effects in BEAS-2B cells, and antimycobacterial activity against Mycobacterium tuberculosis H37Rv and resistant strains were assessed in vitro. Results: The quercetin-rifampicin nanoemulsion (QUE-RIF-NE) showed an average size of 24 nm, zeta potential of −27 mV, and drug recovery rates of 77% (quercetin) and 75% (rifampicin). The formulation was stable and non-cytotoxic at 10⁻⁸ M, reducing IFN-γ production by half and reactive oxygen species production by almost 75% in BEAS-2B cells. It also exhibited antimycobacterial activity against both susceptible and resistant M. tuberculosis strains (MIC ≤ 0.015 µg/mL). Conclusions: QUE-RIF-NE exhibits promising physicochemical stability and dual anti-inflammatory and antimicrobial activity in vitro, demonstrating potential for optimized pulmonary or systemic TB therapy that integrates both anti-inflammatory and antimicrobial effects. Full article

Bromoepiandrosterone (BEA), a synthetic analog of the adrenal steroid DHEA, holds promise as a host-directed therapy for both active and latent tuberculosis (TB). Unlike DHEA, BEA lacks hormonal side effects yet retains potent immunomodulatory activity. It promotes a Th1-skewed immune response by enhancing interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α), critical cytokines for macrophage activation and intracellular control of Mycobacterium tuberculosis (Mtb), while suppressing Th2 cytokines such as IL-4. BEA also inhibits 11β-hydroxysteroid dehydrogenase-1, lowering intracellular cortisol levels and reversing the local immunosuppression commonly seen in TB. These features enable BEA to restore immune competency in TB-infected tissues. In murine TB models, BEA halted bacterial growth, reduced pulmonary inflammation, and synergized with standard anti-TB drugs to enhance bacterial clearance. Additionally, DHEA and its analogues have demonstrated direct antimycobacterial activity, likely by interfering with Mtb mycolic acid synthesis, a property BEA is believed to share. For latent TB, BEA’s ability to sustain Th1-mediated immunity and counteract immune suppression could help maintain latency and prevent reactivation, especially in immunocompromised individuals. By boosting immune surveillance and potentially contributing to bacillary clearance, BEA offers a unique adjunctive approach that complements existing TB treatments without contributing to drug resistance. Its dual function, an immune modulator and antimicrobial agent, supports its use across the TB disease spectrum. These properties position BEA as a novel candidate for host-directed therapy aimed at improving outcomes in both drug-sensitive and drug-resistant TB, as well as therapies aimed at enhancing long-term containment of latent infection. Full article

The emergence of drug resistance remains a major challenge in the treatment of tuberculosis and other mycobacterial infections. To combat the rise in resistance, strategies that reduce the frequency of resistance mutations are urgently needed. Verapamil is a small-molecule compound that can enhance the potency of companion drugs in combination regimen. Here, we investigate if verapamil can decrease the resistance frequency of antimycobacterial drugs. The results show that verapamil significantly reduces the resistance frequency of multiple antimycobacterial agents, including the DNA gyrase inhibitor moxifloxacin, the protein synthesis inhibitor streptomycin, and the RNA polymerase inhibitor rifampicin in Mycobacterium smegmatis. The presence of point mutations in the target was confirmed for moxifloxacin-resistant M. smegmatis. Suppression of resistance evolution against moxifloxacin by verapamil was also found in the slow-growing, pathogenic mycobacteria M. avium and M. tuberculosis. Real-time qPCR analysis in M. smegmatis showed that verapamil treatment downregulates the expression of multiple efflux pump genes and upregulates DNA repair genes. These findings suggest that verapamil exerts a dual role by interfering with efflux pump functionality and by reducing the probability of chromosomal mutations. The combination of these properties may underlie the promise of verapamil as adjuvant to enhance the effectiveness of current antimycobacterial chemotherapy. Full article

Tuberculosis (TB) remains a major global health concern, underscoring the urgent need for innovative therapeutic approaches. In this study, we aimed to identify potential inhibitors of phenyloxazoline synthase MbtB, an essential enzyme involved in the iron acquisition pathway of Mycobacterium tuberculosis and a promising target for drug development. To this end, a curated library of FDA-approved drugs from the ZINC database was systematically screened to uncover compounds with potential inhibitory activity against MbtB.Multiple conformations of the substrate’s transition state structure were utilized as query models. Conformational ensembles for both the query molecules and compounds within the FDA-approved drug library were generated using Balloon (v1.8.2). Virtual screening was then conducted using ShaEP (v1.4.0), which evaluates shape and electrostatic potential similarity, resulting in the identification of several promising candidate inhibitors.Molecular dynamics simulation was performed to understand molecular-level interaction between the top 5 hits and the target protein. Top hits will be procured, testing their anti-TB activity in ion-rich and ion-deprived media, as reported in earlier publications. Full article

Drug-resistant tuberculosis (DR-TB) threatens global TB control. We investigated the prevalence and molecular characteristics of second-line drug resistance among rifampicin (RIF)- and/or isoniazid (INH)-resistant Mycobacterium tuberculosis complex (MTBC) isolates in São Paulo, Brazil, using the MTBDRsl v. 2.0 line-probe assay. MTBC isolates RIF- and/or INH-resistant by GenoType MTBDRplus or phenotypic testing (2019–2021) were subsequently tested by MTBDRsl for fluoroquinolone (FQ) and injectable drugs (capreomycin, amikacin, kanamycin) resistance. Isolates with inferred mutations underwent Sanger sequencing. Of 13,557 isolates, 728 (5.4%) were RIF- and/or INH-resistant (297 INH-R, 235 RIF-R, 196 MDR). Among them, 623 (85.6%) were tested by MTBDRsl; 582 (93.4%) showed no additional resistance, while 41 (6.6%) carried mutations. FQ resistance was detected in 38 isolates (92.7%), mostly in gyrA (n = 35). Three isolates with gyrB mutations were wild-type by sequencing. Two MDR isolates harbored the rrs a1401g mutation, and one also harbored gyrA D94G. Sequencing confirmed resistance in 38 of 41 isolates. Most MDR strains with second-line mutations (n = 32/33; 97%) were pre-XDR. Affected patients were predominantly male (68.4%), with pulmonary TB (92.1%), and unfavorable outcomes (39.5%). Second-line resistance prevalence was low overall, but FQ resistance was high among MDR isolates. Findings support integrating molecular and sequencing-based tools for accurate detection and management of DR-TB. Full article

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a global health challenge, partly due to the prolonged duration and toxicity of standard antibiotic regimens. Adjunctive therapies that enhance antimicrobial efficacy and modulate host immunity are urgently needed. Curcumin, a natural bioactive compound derived from Curcuma longa, possesses broad therapeutic properties, including anti-inflammatory, antioxidant, antibacterial, and antiviral effects. This study evaluated the effects of curcumin in combination with first- and second-line antibiotics against Mtb in both in vitro and in vivo models. Our results demonstrated that curcumin exerts direct antibacterial activity against both the drug-sensitive H37Rv strain and a multidrug-resistant (MDR) clinical isolate. Furthermore, curcumin synergized with conventional antibiotics, enhancing bacterial clearance in infected macrophages while promoting the production of IL-12, a key cytokine in protective immune responses. In a murine model of progressive pulmonary TB, combination therapy with curcumin and first-line antibiotics significantly reduced the lung bacterial burden and improved behavioral outcomes compared to antibiotic treatment alone. These findings suggest that curcumin acts through both direct antimicrobial mechanisms and immune modulation, supporting its potential as an adjunctive therapy agent for TB. Future studies should focus on optimizing curcumin formulation, dosing, and bioavailability to facilitate the clinical translation of this compound. Full article

Drug-resistant Mycobacterium tuberculosis (Mtb) remains a major global health challenge, prompting the need for new therapeutics targeting essential bacterial proteins. The caseinolytic protein C1 (ClpC1) is a promising drug target, and accurate measurement of its ATPase activity is critical for understanding drug mechanisms. We optimized a sensitive luminescence-based ATPase assay and evaluated ClpC1 constructs with various tag positions and truncations. N-terminal tagging significantly impaired enzymatic activity, whereas C-terminal tagging had no effect; truncated domains showed reduced activity compared to native full-length (FL) ClpC1. Using the native FL-ClpC1, we assessed ecumicin (ECU) and five analogs via ATPase activity and surface plasmon resonance (SPR), using rufomycin (RUF) and cyclomarin A (CYMA) as controls. RUF and CYMA bound tightly (K_D = 0.006–0.023 µM) and inhibited Mtb growth (MIC₉₀ = 0.02–0.094 µM) but modestly stimulated ATPase activity (≤2-fold). In contrast, ECU and its analogs strongly enhanced ATPase activity (4–9-fold) despite slightly weaker binding (K_D = 0.042–0.80 µM) and growth inhibition (MIC₉₀ = 0.19 µM). The partial correlation among AC₅₀, K_D, and MIC values highlights the complementary value of enzymatic, biophysical, and cellular assays. Our assay platform enables mechanistic characterization of ClpC1-targeting compounds and supports rational antitubercular drug development. Full article

Tuberculosis (TB) probably returned to being the world’s leading cause of death from a single infectious agent after three years during which it was replaced by COVID-19. Currently, there are two major, closely related challenges in TB treatment: a large number of cases of drug-resistant TB, as well as cases complicated by severe comorbidities. Materials and Methods: Our study included 219 patients with pulmonary multidrug-resistant TB (MDR-TB) who were treated in several clinics in St. Petersburg, Russian Federation. Of these patients, 47.0% had extensively drug-resistant TB (XDR-TB), and 48.4% had severe comorbidities. Univariate and multivariate exploratory analyses were performed to hypothesize factors affecting treatment success. Results: Both extensive drug resistance (XDR-TB) and the presence of comorbidity were significantly associated with a lower probability of successful treatment: OR = 0.56 (CI: 0.32–0.96, p = 0.033) and OR = 0.53 (CI: 0.30–0.91, p = 0.020), respectively. The use of bedaquiline was significantly associated with successful treatment in cases of XDR-TB: OR = 4.15 (CI: 1.32–16.20, p = 0.012). Only an insignificant opposite effect was identified for cases of non-XDR-TB: OR = 0.77 (p = 0.62). Resistance to thioamides was associated with unsuccessful treatment in cases complicated by comorbidity: OR = 0.46 (CI: 0.21–0.99, p = 0.044). Again, an only insignificant opposite effect was identified for cases without comorbidities: OR = 1.11 (p = 0.81). Almost all the patterns described above were replicated in the multivariate model. The following two differences with the univariate results were observed. First, the association between the use of bedaquiline and successful treatment became even more pronounced, and, as before, this was true only for XDR-TB: OR = 6.51 (CI: 1.98–26.04, p = 0.0036) for XDR-TB, and OR = 0.99 (p = 0.98) for non-XDR-TB. Second, the impact of comorbidities on treatment success remained significant only in conjunction with thioamide resistance. In addition, we found that the association between resistance to thioamides and unsuccessful treatment was especially pronounced in cases complicated by heart disease: OR = 0 (CI: 0–0.79, p = 0.0088). Conclusions: We confirmed that both XDR-TB and the presence of comorbidities are serious challenges in the treatment of tuberculosis. We also have reason to hypothesize that, first, bedaquiline can be a much more crucial component of therapy in cases of XDR-TB than in other cases of MDR-TB and, second, thioamides can play a positive role in cases complicated by comorbidities, especially by heart diseases. These findings should be considered as weak hypotheses that require further verification using independent data, as our analysis was exploratory rather than confirmatory. Full article

Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), remains one of the most devastating infectious diseases worldwide, with rising multidrug resistance limiting the effectiveness of conventional treatments. Novel therapeutic approaches are urgently needed to complement or replace existing regimens. Among emerging candidates, antimicrobial peptides (AMPs) stand out as versatile molecules capable of exerting direct antimycobacterial effects while also modulating the host immune response. This review explores peptide-based strategies against TB, with a focus on four major axes of innovation. First, we examine host-directed pathways, including the vitamin D–cathelicidin axis and other immunomodulatory mechanisms and their regulatory role in the induction of endogenous AMPs such as cathelicidin LL-37, which contributes to host-directed defense. Second, we discuss peptide-based vaccines designed to elicit robust and durable protective immunity, representing a complementary alternative to classical vaccine approaches. Third, we highlight the synergistic potential of AMPs in combination with first-line and second-line anti-TB drugs, aiming to restore or enhance bactericidal activity against resistant strains. Finally, we analyze technological platforms, including nanocarriers and inhalable formulations, that enable targeted pulmonary delivery, improve peptide stability, and enhance bioavailability. By integrating molecular design, immune modulation, and advanced delivery systems, peptide-based strategies provide a multifaceted approach to overcoming the limitations of current TB therapy. Collectively, these advances position AMPs not only as promising standalone agents but also as key components in combination and host-directed therapies, with strong potential to reshape the future clinical management of tuberculosis. Full article