Drug-resistant Tuberculosis Strains Research Articles

The rising tide of tuberculosis in Pakistan: Factors, impact, and multi-faceted approaches for prevention and control.

Tuberculosis (TB) remains a major public health concern in Pakistan, which is ranked fifth among high-burden TB nations worldwide. The growing frequency of drug-resistant TB strains, particularly multidrug-resistant TB (MDR-TB), creates new obstacles. Socioeconomic factors, a lack of awareness, and inadequate healthcare infrastructure all contribute to the spread of the disease. This study investigates the mechanisms contributing to the growth in tuberculosis cases in Pakistan, the implications for public health, and multifaceted approaches to prevention and control. A comprehensive literature study was undertaken, including an analysis of peer-reviewed articles, World Health Organization (WHO) data, and government sources, to identify factors driving tuberculosis prevalence, control issues, and disease-fighting tactics.Result: Several factors like Poverty, overcrowding, malnutrition, stigma, and restricted access to healthcare services are all factors contributing to an increase in tuberculosis incidence in Pakistan. The prevalence of MDR-TB, along with a lack of an integrated healthcare response, complicates efforts to contain the disease's spread. Tuberculosis has a profound social, mental, and financial impact on individuals and communities. Public health efforts, such as the National Tuberculosis Control Program (NTP) and international partnerships, have been created to eradicate tuberculosis, although considerable hurdles persist. This study investigates the mechanisms contributing to the growth in tuberculosis cases in Pakistan, the implications for public health, and multifaceted approaches to prevention and control.

Development and Evaluation of Bis-benzothiazoles as a New Class of Benzothiazoles Targeting DprE1 as Antitubercular Agents.

Benzothiazole-bearing compounds have emerged as potential noncovalent DprE1 (decaprenylphosphoryl-β-d-ribose-2'-epimerase) inhibitors active against Mycobacterium tuberculosis. Based on structure-based virtual screening (PDB ID: 4KW5), a focused library of thirty-one skeletally diverse benzothiazole amides was prepared, and the compounds were assessed for their antitubercular activity against M.tb H37Ra. Most potent compounds 3b and 3n were further evaluated against the M.tb H37Rv strain by the microdilution assay method. Among the compounds evaluated, bis-benzothiazole amide 3n emerged as a hit molecule and demonstrated promising antitubercular activity with minimum inhibitory concentration (MIC) values of 0.45 μg/mL and 8.0 μg/mL against H37Ra and H37Rv, respectively. Based on the preliminary hit molecule (3n), a focused library of 12 more bis-benzothiazole amide derivatives was further prepared by varying the substituents on either side to obtain new leads and generate a structure-activity relationship (SAR). Among these compounds, 6a, 6c, and 6d demonstrated remarkable antitubercular activity with MIC values of 0.5 μg/mL against H37Ra and 1.0, 2.0, and 8.0 μg/mL against H37Rv, respectively. The most active compound, 6a, also displayed significant efficacy against four drug-resistant tuberculosis strains. Compound 6a was assessed for in vitro cytotoxicity against the HepG2 cell line, and it displayed insignificant cytotoxicity. Furthermore, time-kill kinetic studies demonstrated time- and dose-dependent bactericidal activity of this compound. The GFP release assay revealed that compound 6a targets the inhibition of a cell wall component. SNPs in dprE-1 gene assessment revealed that compound 6a binds to tyrosine at position 314 of DprE1 and replaces it with histidine, causing resistance similar to that of standard TCA1. In silico docking studies further suggest that the strong noncovalent interactions of these compounds may lead to the development of potent noncovalent DprE1 inhibitors.

Overview of Tuberculosis: Causes, Symptoms and Risk Factors

Tuberculosis (TB) remains a global health threat, exacerbated by factors such as drug resistance, co-infections, and social determinants of health. This comprehensive review examines various aspects of TB, including epidemiology, pathophysiology, diagnosis, treatment, prevention, and control measures. The bacterium Mycobacterium tuberculosis causes TB and primarily affects the lungs, although it can also affect other organs. Risk factors for TB include poverty, malnutrition, overcrowded living conditions, and immunocompromised states such as HIV/AIDS. Symptoms of TB include cough, fever, weight loss, and night sweats, but can vary depending on the site of infection. Diagnosis typically involves clinical evaluation, imaging studies, and microbiological testing, with rapid molecular tests such as the Xpert MTB/RIF assay revolutionizing TB diagnostics. Treatment consists of multidrug therapy for six to nine months, with drug-resistant TB requiring longer and more complex regimens. Prevention and control efforts focus on early case detection, treatment adherence, infection control measures, and Bacille Calmette-Guérin (BCG) vaccine vaccination. TB research and innovation aim to develop new diagnostics, drugs, and vaccines to improve TB control and treatment outcomes. Challenges to TB control include stigma, healthcare access barriers, and the rise of drug-resistant TB strains. Collaboration and advocacy efforts are essential for addressing TB in special populations, high-risk settings, and co-infection scenarios. Integrating a One Health approach, harnessing technology, and addressing climate change impacts is critical for advancing TB control efforts and achieving the goal of ending the global TB epidemic.

Can We Exploit Inflammasomes for Host-Directed Therapy in the Fight against Mycobacterium tuberculosis Infection?

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M. tb), is a major global health issue, with around 10 million new cases annually. Advances in TB immunology have improved our understanding of host signaling pathways, leading to innovative therapeutic strategies. Inflammasomes, protein complexes organized by cytosolic pattern recognition receptors (PRRs), play a crucial role in the immune response to M. tb by activating caspase 1, which matures proinflammatory cytokines IL1β and IL18. While inflammation is necessary to fight infection, excessive or dysregulated inflammation can cause tissue damage, highlighting the need for precise inflammasome regulation. Drug-resistant TB strains have spurred research into adjunctive host-directed therapies (HDTs) that target inflammasome pathways to control inflammation. Canonical and non-canonical inflammasome pathways can trigger excessive inflammation, leading to immune system exhaustion and M. tb spread. Novel HDT interventions can leverage precision medicine by tailoring treatments to individual inflammasome responses. Studies show that medicinal plant derivatives like silybin, andrographolide, and micheliolide and small molecules such as OLT1177, INF39, CY-09, JJ002, Ac-YVAD-cmk, TAK-242, and MCC950 can modulate inflammasome activation. Molecular tools like gene silencing and knockouts may also be used for severe TB cases. This review explores these strategies as potential adjunctive HDTs in fighting TB.

Synthesis of indole-functionalized isoniazid conjugates with potent antimycobacterial and antioxidant efficacy.

Aim: Developing potent medicinal alternates for tuberculosis (TB) is highly desirable due to the advent of drug-resistant lethal TB strains.Methods & results: Novel indole-isoniazid integrates have been synthesized with promising antimycobacterial action against the H37Rv strain, and the nitro analogs 4e and 4j show the highest efficacy with a minimum inhibitory concentration of 1.25μg/ml. The molecular docking studies against InhA support the experimental findings. Indole conjugates display remarkable radical quenching efficiency, and compounds 4e and 4j demonstrate maximum IC50 values of 50.19 and 52.45μg/ml, respectively. Pharmacokinetic analysis anticipated appreciable druggability for the title compounds.Conclusion: The notable bioaction of the indole-isoniazid templates projects them as potential lead in developing anti-TB medications with synergetic antioxidant action.

Electrolyte disruption in drug-resistant tuberculosis: Managing risks for improved treatment outcomes

This editorial sheds light on the critical issue of electrolyte imbalance in drug-resistant tuberculosis (TB), a significant challenge exacerbated by the prolonged and intensive treatment regimens required for multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB strains. The use of second-line drugs, such as fluoroquinolones and aminoglycosides, necessary in these cases, often disrupts electrolyte homeostasis, leading to complications like hypokalemia and hypomagnesaemia. These disturbances can pose serious risks to patients, including cardiac arrhythmias and renal dysfunction. Beyond medication effects, TB itself induces systemic inflammation and metabolic alterations, further complicating electrolyte balance. Effective management necessitates vigilant monitoring of electrolyte levels throughout treatment, coupled with renal function assessments and nutritional support.

Targeting mycobacterial efflux system to enhance tuberculosis therapy

The worldwide health epidemic of tuberculosis (TB) persists. It still claims millions of lives each year despite medical breakthroughs. Long-term therapies, drug-resistant TB strains, and co-infections with conditions like HIV necessitate novel approaches. The use of Mycobacterium tuberculosis (Mtb) efflux pumps, which actively expel drugs and decrease their effectiveness, is one such approach. EPIs (Efflux Pump Inhibitors) have the potential to treat tuberculosis. This review offers insights into Mtb's immune evasion mechanisms, including its strong cell wall, granuloma formation, immunological modulation, and dormancy, as well as TB epidemiology, worldwide eradication efforts, and those processes. Dissecting Efflux Pumps highlights their significance in drug resistance, particularly against first-line TB medications. Efflux pumps are notorious for causing antibiotic resistance. EPIs may have benefits such as increased drug efficacy, resistance reversal, shortened treatment durations, less toxicity, improved adherence, and targeting of latent TB. The effectiveness of various EPI classes, including phenylalkylamines, protonophores, phenothiazines, and plant-derived derivatives, against Mtb growth and efflux pumps is evaluated. The creation of effective EPIs, a clearer understanding of efflux pump control, and essential clinical trials for validation remain obstacles.

Apramycin has high in vitro activity against Mycobacterium tuberculosis.

Introduction. Aminoglycoside antibiotics such as amikacin and kanamycin are important components in the treatment of Mycobacterium tuberculosis (Mtb) infection. However, more and more clinical strains are found to be aminoglycoside antibiotic-resistant. Apramycin is another kind of aminoglycoside antibiotic that is commonly used to treat infections in animals.Hypothesis. Apramycin may have in vitro activity against Mtb.Aim. This study aims to evaluate the efficacy of apramycin against Mtb in vitro and determine its epidemiological cut-off (ECOFF) value.Methodology. One hundred Mtb isolates, including 17 pansusceptible and 83 drug-resistant tuberculosis (DR-TB) strains, were analysed for apramycin resistance using the MIC assay.Results. Apramycin exhibited significant inhibitory activity against Mtb clinical isolates, with an MIC50 of 0.5 μg ml-1 and an MIC90 of 1 μg ml-1. We determined the tentative ECOFF value as 1 µg ml-1 for apramycin. The resistant rates of multidrug-resistant tuberculosis (MDR-TB), pre-extensively drug-resistant (pre-XDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) strains were 12.12 % (4/33), 20.69 % (6/29) and 66.67 % (14/21), respectively. The rrs gene A1401G is associated with apramycin resistance, as well as the cross-resistance between apramycin and other aminoglycosides.Conclusion. Apramycin shows high in vitro activity against the Mtb clinical isolates, especially the MDR-TB clinical isolates. This encouraging discovery calls for more research on the functions of apramycin in vivo and as a possible antibiotic for the treatment of drug-resistant TB.

Factors associated with underreporting of tuberculosis cases among private healthcare providers in Semarang City

Tuberculosis (TB) continues to be a global public health challenge, with accurate case reporting being crucial for the implementation of effective control measures. In Semarang City, Indonesia, private healthcare providers play a pivotal role, yet the under-reporting of TB cases in this sector compromises the management and containment of the disease. This study investigates the factors influencing the under-reporting of TB cases among private healthcare providers and explores their consequences for public health strategies. The primary aim of this research is to elucidate the relationship between various determinants such as physicians’ knowledge of TB notification protocols, their commitment to notification processes, the availability of dedicated staff for notification, incentive mechanisms, and the notification format used, and the phenomenon of TB case under-reporting. Methods: Employing the Spearman correlation coefficient, this study evaluates the associations between the identified factors and the under-reporting of TB cases. The findings indicate significant correlations between under-reporting of TB cases and several variables: the physicians' awareness of notification requirements, their commitment to notification procedures, the existence of incentives, the appointment of designated staff for notification tasks, and the format of the notification system (Sig < 0.05). Discussion: The under-reporting of TB cases hinders accurate disease surveillance and timely intervention, thereby perpetuating transmission and increasing the risk of drug-resistant TB strains. The results underscore the necessity for targeted interventions aimed at enhancing TB reporting practices among private healthcare providers. Enhancing these practices is crucial for strengthening the overall TB control strategy and protecting public health.

Large-scale statistical analysis of Mycobacterium tuberculosis genome sequences identifies compensatory mutations associated with multi-drug resistance

Tuberculosis (TB), caused by Mycobacterium tuberculosis, has a significant impact on global health worldwide. The development of multi-drug resistant strains that are resistant to the first-line drugs isoniazid and rifampicin threatens public health security. Rifampicin and isoniazid resistance are largely underpinned by mutations in rpoB and katG respectively and are associated with fitness costs. Compensatory mutations are considered to alleviate these fitness costs and have been observed in rpoC/rpoA (rifampicin) and oxyR’-ahpC (isoniazid). We developed a framework (CompMut-TB) to detect compensatory mutations from whole genome sequences from a large dataset comprised of 18,396 M. tuberculosis samples. We performed association analysis (Fisher’s exact tests) to identify pairs of mutations that are associated with drug-resistance, followed by mediation analysis to identify complementary or full mediators of drug-resistance. The analyses revealed several potential mutations in rpoC (N = 47), rpoA (N = 4), and oxyR’-ahpC (N = 7) that were considered either ‘highly likely’ or ‘likely’ to confer compensatory effects on drug-resistance, including mutations that have previously been reported and validated. Overall, we have developed the CompMut-TB framework which can assist with identifying compensatory mutations which is important for more precise genome-based profiling of drug-resistant TB strains and to further understanding of the evolutionary mechanisms that underpin drug-resistance.

Tuberculosis-diabetes comorbidities: Mechanistic insights for clinical considerations and treatment challenges.

Tuberculosis (TB) remains a leading cause of death among infectious diseases, particularly in poor countries. Viral infections, multidrug-resistant and ex-tensively drug-resistant TB strains, as well as the coexistence of chronic illnesses such as diabetes mellitus (DM) greatly aggravate TB morbidity and mortality. DM [particularly type 2 DM (T2DM)] and TB have converged making their control even more challenging. Two contemporary global epidemics, TB-DM behaves like a syndemic, a synergistic confluence of two highly prevalent diseases. T2DM is a risk factor for developing more severe forms of multi-drug resistant-TB and TB recurrence after preventive treatment. Since a bidirectional relationship exists between TB and DM, it is necessary to concurrently treat both, and promote recommendations for the joint management of both diseases. There are also some drug-drug interactions resulting in adverse treatment outcomes in TB-DM patients including treatment failure, and reinfection. In addition, autophagy may play a role in these comorbidities. Therefore, the TB-DM comorbidities present several health challenges, requiring a focus on multidisciplinary collaboration and integrated strategies, to effectively deal with this double burden. To effectively manage the comorbidity, further screening in affected countries, more suitable drugs, and better treatment strategies are required.

Mathematical modeling of two strains tuberculosis and COVID-19 vaccination model: a co-infection study with cost-effectiveness analysis

Tuberculosis and COVID-19 co-infection is currently the major issue of public health in many nations, including Ghana. Therefore, to explore the effects of the two Tuberculosis strains on COVID-19, we suggest a Tuberculosis and COVID-19 co-infection model. The study also provides the most economical and effective control methods to reduce the co-infection of tuberculosis and COVID-19. Based on the behavioral patterns of the two Tuberculosis strains and COVID-19 reproduction numbers, the stability of the co-infection model is examined. We explore the sensitivity of the parameters to examine the effect of the drug-resistant and drug-sensitive strain of Tuberculosis on the co-infection of COVID-19. We determine the most cost-effective and optimal treatment strategies that aim to maximize outcomes while minimizing tuberculosis and/or COVID-19 incidences, cost-effectiveness, and optimization approaches. The outcomes of this work contribute to a better understanding of Tuberculosis and COVID-19 epidemiology and provide insights into implementing interventions needed to minimize Tuberculosis and COVID-19 burden in similar settings worldwide.

Applications of Inorganic Nanomaterials against Tuberculosis: A Comprehensive Review.

Tuberculosis (TB) continues to pose a significant global health threat, with millions of new infections recorded annually. Current treatment strategies, such as Directly Observed Treatment (DOT), face challenges, including patient non-compliance and the emergence of drug-resistant TB strains. In response to these obstacles, innovative approaches utilizing inorganic/metallic nanomaterials have been developed to enhance drug delivery to target alveolar macrophages, where Mycobacterium tuberculosis resides. These nanomaterials have shown effectiveness against various strains of TB, offering benefits such as improved drug efficacy, minimized side effects, and sustained drug release at the infection site. This comprehensive review explores the applications of different metal nanoparticles, metal oxide nanoparticles, and metal-metal oxide hybrid nanoparticles in the management of TB, including multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. The synergistic effects of combining inorganic nanoparticles with conventional anti-TB drugs have demonstrated promising results in combating TB infections. Further research and development in this field hold great promise for overcoming the challenges faced in current TB therapy and improving patient outcomes.

Exploring Genomic Patterns to Identify Drug-Resistant TB: A Comprehensive Study of Age, Gender, Lineage, and Outcome

Background: Tuberculosis (TB) is a prevalent bacterial infection caused by Mycobacterium tuberculosis (Mtb), primarily affecting the lungs, with rising incidence rates. Drug-resistant TB strains, including multidrug-resistant (MDR) and extensively drug-resistant (XDR) types, pose challenges with poor treatment success rates and increased mortality. Demographic factors and genomic patterns contribute to drug resistance, emphasizing the need for new drugs targeting specific genomic patterns.Methods: This study analyzes the impact of demographics, treatment outcomes, and genomic mutations on drug-resistant TB using pattern identification techniques and whole-genome sequencing to discover therapeutic targets. This study primarily focused on the identification and analysis of MDR and XDR strains, considering various demographic characteristics and treatment outcomes. A dataset comprising 2,602 observations was utilized, and pattern recognition techniques were employed to identify significant features. Additionally, the study employs the whole-genome sequencing (WGS) pipeline to identify single nucleotide polymorphisms (SNPs) that result in new mutations in drug-resistant Mtb strains.Results: The findings of the study revealed that XDR and MDR non-XDR TB were the most prevalent types of drug resistance, and they were associated with unfavorable treatment outcomes, including death or treatment failure. Males exhibited a higher susceptibility to both XDR and MDR non-XDR TB compared to females. The age of onset for both types of resistance was approximately 40 years. Among the observed variants in 31 commonly occurring genes,Conclusion: These findings introduce a novel set of therapeutic targets specific to MDR and XDR Mtb types, which warrant further investigation for potential therapeutic interventions.Keywords: Tuberculosis; Drug Resistance; Multidrug resistance; Demographics; Dataset; Gene; Mutations

Structure-guided identification and characterization of potent inhibitors targeting PhoP and MtrA to combat mycobacteria

Mycobacteria are causative agents of tuberculosis (TB), which is a global health concern. Drug-resistant TB strains are rapidly emerging, thereby necessitating the urgent development of new drugs. Two-component signal transduction systems (TCSs) are signaling pathways involved in the regulation of various bacterial behaviors and responses to environmental stimuli. Applying specific inhibitors of TCSs can disrupt bacterial signaling, growth, and virulence, and can help combat drug-resistant TB. We conducted a comprehensive pharmacophore-based inhibitor screening and biochemical and biophysical examinations to identify, characterize, and validate potential inhibitors targeting the response regulators PhoP and MtrA of mycobacteria. The constructed pharmacophore model Phar-PR-n4 identified effective inhibitors of formation of the PhoP–DNA complex: ST132 (IC50 = 29 ± 1.6 µM) and ST166 (IC50 = 18 ± 1.3 µM). ST166 (KD = 18.4 ± 4.3 μM) and ST132 (KD = 14.5 ± 0.1 μM) strongly targeted PhoP in a slow-on, slow-off manner. The inhibitory potency and binding affinity of ST166 and ST132 for MtrAC were comparable to those of PhoP. Structural analyses and molecular dynamics simulations revealed that ST166 and ST132 mainly interact with the α8-helix and C-terminal β-hairpin of PhoP, with functionally essential residue hotspots for structure-based inhibitor optimization. Moreover, ST166 has in vitro antibacterial activity against Macrobacterium marinum. Thus, ST166, with its characteristic 1,2,5,6-tetrathiocane and terminal sulphonic groups, has excellent potential as a candidate for the development of novel antimicrobial agents to combat pathogenic mycobacteria.

Emerging bedaquiline resistance: A threat to the global fight against drug-resistant tuberculosis

Bedaquiline resistance is increasingly observed in the treatment of rifampicin-resistant tuberculosis (TB), yet standardized regimens for managing bedaquiline-resistant TB are lacking. Studies indicate a high proportion of bedaquiline-resistant cases have previously been treated for TB, and often involve strains resistant to quinolones. Regular monitoring of the culture status in patients receiving bedaquiline resistance treatment is advised. Methods such as experimental evolution, protein modeling, genome sequencing, and phenotypic analysis have been instrumental in identifying the mechanisms of bedaquiline resistance. Specifically, variants in the Rv0678 transcriptional repressor of the MmpS5-MmpL5 efflux system are linked to this type of resistance. Bayesian probability estimates show promise in determining the genotypic–phenotypic association for bedaquiline resistance, suggesting potential utility in clinical practice. Future research should explore the practical application of Bayesian probabilities in managing bedaquiline resistance. Sequencing-based technologies are anticipated to play a vital role in the early detection and management of drug-resistant TB strains.

Identification of Chemical Scaffolds Targeting Drug-Resistant and Latent Mycobacterium tuberculosis through High-Throughput Whole-Cell Screening.

Identification of structurally unique chemical entities targeting unexplored bacterial targets is a prerequisite to combat increasing drug resistance against Mycobacterium tuberculosis. This study employed a whole-cell screening approach as an initial filter to scrutinize a 10,000-compound chemical library, resulting in the discovery of seven potent compounds with MIC values ranging from 1.56 to 25 μM. These compounds were categorized into four distinct chemical groups. Remarkably, they demonstrated efficacy against drug-resistant and nonreplicating tuberculosis strains, highlighting their effectiveness across different infection states. With a favorable selectivity index (>10), these compounds showed a safe therapeutic range and exhibited potency in an intracellular model of Mtb infection, mimicking the in vivo setup. Combining these identified hits with established anti-TB drugs revealed additive effects with rifampicin, isoniazid, and bedaquiline. Notably, IIIM-IDD-01 exhibited synergy with isoniazid and bedaquiline, likely due to their complementary mechanisms of targeting Mtb. Most potent hits, IIIM-IDD-01 and IIIM-IDD-02, displayed time- and concentration-dependent killing of Mtb. Mechanistic insights were sought through SEM and docking studies, although comprehensive evaluation is ongoing to unravel the hits' specific targets and modes of action. The hits demonstrated favorable pharmacokinetic properties (ADME-Tox) and showed a low risk of adverse effects, along with a predicted high level of oral bioavailability. These promising hits can serve as an initial basis for subsequent medicinal chemistry endeavors aimed at developing a new series of anti-TB agents. Moreover, the study affirms the significance of high-throughput in vitro assays for the TB drug discovery. It also emphasizes the necessity of targeting diverse TB strains to address the heterogeneity of tuberculosis bacteria.

Tuberculosis Prevalence Trends from a Predictive Modelling Study - 10 High-Burden Countries, 1980-2035.

Given the challenges presented by drug-resistant strains of tuberculosis (TB) and the rising mobility of the population, achieving the objective of eradicating TB appears uncertain. The examination of TB incidence trends in 10 high-burden countries (HBCs) indicated a steady rise in cases, with India and China jointly accounting for nearly 70% of the burden. Projections for the future show diverse trajectories in these countries, with potential difficulties in reaching the TB elimination target, especially in Nigeria, Congo, and South Africa. The number of TB cases is on the rise. It is crucial to learn from successful strategies to improve TB prevention and control worldwide through collaborative efforts.

Improvement in Outcomes with a New Bedaquiline-based Regimen in Postoperative Cases of Drug-resistant Tuberculosis of the Spine: A Case Series

The incidence of drug-resistant strains of Tuberculosis (TB) is rising at an alarming rate. With the emergence of newer drug-resistant strains, managing the disease with existing antitubercular agents is becoming increasingly difficult. Few studies exist regarding the treatment of drug-resistant TB of the spine using a Bedaquiline-based regimen. Therefore, the efficacy of shorter regimens with novel drugs such as Bedaquiline and Delamanid in drug-resistant TB of the spine must be analysed. The present case series highlights the outcomes of a newer Bedaquiline-based antitubercular regimen in postoperative cases of drug-resistant TB of the spine. All three cases discussed in this study-54-year-old female, 12-year-old female, and 19-year-old female patients-had a clinical and radiological diagnosis of TB of the spine with significant neurodeficits. They underwent decompression and instrumentation surgery. Postoperatively, all three were diagnosed with drug-resistant TB and were started on a Bedaquiline-based antitubercular regimen. Subsequently, all the patients showed significant improvement in neurodeficits with no radiological evidence of recurrence. Therefore, Bedaquiline might play an important role in the future management of drug-resistant spinal TB.

In silico Screening of Food and Drug Administration-approved Compounds against Trehalose 2-sulfotransferase (Rv0295c) in Mycobacterium tuberculosis: Insights from Molecular Docking and Dynamics Simulations.

Tuberculosis (TB) remains a prominent global health challenge, distinguished by substantial occurrences of infection and death. The upsurge of drug-resistant TB strains underscores the urgency to identify novel therapeutic targets and repurpose existing compounds. Rv0295c is a potentially druggable enzyme involved in cell wall biosynthesis and virulence. We evaluated the inhibitory activity of Food and Drug Administration (FDA)-approved compounds against Rv0295c of Mycobacterium tuberculosis, employing molecular docking, ADME evaluation, and dynamics simulations. The study screened 1800 FDA-approved compounds and selected the top five compounds with the highest docking scores. Following this, we subjected the initially screened ligands to ADME analysis based on their dock scores. In addition, the compound exhibited the highest binding affinity chosen for molecular dynamics (MD) simulation to investigate the dynamic behavior of the ligand-receptor complex. Dihydroergotamine (CHEMBL1732) exhibited the highest binding affinity (-12.8 kcal/mol) for Rv0295c within this set of compounds. We evaluated the stability and binding modes of the complex over extended simulation trajectories. Our in silico analysis demonstrates that FDA-approved drugs can serve as potential Rv0295c inhibitors through repurposing. The combination of molecular docking and MD simulation offers a comprehensive understanding of the interactions between ligands and the protein target, providing valuable guidance for further experimental validation. Identifying Rv0295c inhibitors may contribute to new anti-TB drugs.