Multidrug-resistant Tuberculosis Research Articles

Study of Knowledge, Attitude, and Practices of Use of Masks among Health-care Workers at a Tertiary Care Center in Mumbai

ABSTRACT Introduction: Airborne transmission of infectious diseases poses a significant public health challenge. Nosocomial outbreaks of airborne infections such as influenza H1N1, H5N1, and drug-resistant tuberculosis (TB) variants have been documented, with substantial morbidity and mortality attributed to inadequate airborne infection control strategies. N-95 respirators and surgical masks (face masks) are the examples of personal protective equipment that are used to protect the wearer from airborne particles and liquid contamination of the face. Aim and Objectives: The aim of this study was to assess the knowledge, practices, and attitude of health-care workers (HCWs) regarding the use of mask, especially N-95 mask. Materials and Methods: A prospective, was conducted over a period of 6 months at a tertiary care hospital. This study was carried out in the department of microbiology of a tertiary care hospital over a period of 6 months. A total of 500 HCWs from various departments of the hospital were included in the study. HCWs were given a questionnaire based on N-95 respirator usage, and participation was voluntary. Results: The analysis of survey data provides insightful perspectives on respondents’ comprehension and attitudes toward airborne infection transmission and the usage of N-95 masks. 68.6% of respondents recognized that all listed diseases (measles, TB, and chickenpox) were spread by the airborne route. 55.6% of respondents correctly acknowledged that all masks, including surgical masks, N-95 masks, and cotton masks, do not offer airborne protection. 76.0% of respondents acknowledged that N-95 masks possess a high filtration efficiency against 0.3-micron particles, 58.3% correctly identified that “N” in N-95 stands for “not resistant to oil,” and 90.8% acknowledged that the N-95 respirator as the most common type of respirators. 41.7% correctly acknowledged that N-95 masks with an exhalation valve are not recommended for use. 22.2% of respondents incorrectly believe that wearing a face mask can lead to carbon dioxide poisoning, and 52.1% of respondents correctly identified that pulmonary TB patients need not be provided with N-95 masks in isolation rooms. 76.8% of respondents understood that fit testing is required every time one dons an N-95 mask. 95.5% of respondents recognized the necessity of hand hygiene before donning and after doffing N-95 masks. 82.7% of respondents agreed regarding the necessity for consultation before N-95 mask usage for chronic lung disease and asthma patients. 93.7% are aware that there is a protocol for donning and doffing N-95 masks. 71.3% of respondents understood that extended use involves wearing the same N-95 respirator for repeated close contact encounters without removing the mask between patient encounters, while 64.4% correctly define reuse as using the same N-95 respirator for multiple encounters but removing it after each encounter.

Clinical profiles of multidrug-resistant and rifampicin-monoresistant tuberculosis in Korea, 2018-2021: a nationwide cross-sectional study

Clinical profiles of multidrug-resistant and rifampicin-monoresistant tuberculosis in Korea, 2018-2021: a nationwide cross-sectional study

Challenges and potential solutions for cycloserine dosing in patients with sepsis undergoing continuous renal replacement therapy

Continuous kidney replacement therapy (CRRT) is a special form of dialysis, which has more significant advantages than traditional intermittent hemodialysis in treating critically ill patients. The impact of CRRT and disease complexity on drug clearance in critically ill patients has been reported in several studies, nevertheless, the pharmacokinetic changes of cycloserine in patients with sepsis undergoing CRRT have not been reported. Here, we report a case of a 52-year-old man with septic shock and severe multidrug-resistant tuberculosis who underwent anti-TB therapy. The patient's anti-TB regimen included linezolid, clofazimine, cycloserine, and bedaquiline. Following continuous administration for 14 days, the patient was treated with CRRT due to acid-base imbalance and acute renal failure. Blood samples were collected at 0, 2, 4, 6, 10, and 12 hours following cycloserine administration (CRRT was initiated two hours after administration). Changes in plasma concentration of cycloserine before and after the CRRT were measured. The peak concentration of cycloserine was 39.93 mg/L with a trough concentration of 7.90 mg/L, and the AUC0-12h was 294.36 mg•h/L. These findings firstly suggested that the pharmacokinetics of cycloserine may be influenced by sepsis and CRRT therapy, and cycloserine doses may need to be increased during CRRT therapy in patients with sepsis.

Modeling spread and control of multidrug-resistant tuberculosis in India

Modeling spread and control of multidrug-resistant tuberculosis in India

Adverse Drug Reactions During Intensive Phase of Treatment Among Multi- Drug Resistant Tuberculosis Cases Registered at a DR-TB Centre of Southern India

Adverse Drug Reactions During Intensive Phase of Treatment Among Multi- Drug Resistant Tuberculosis Cases Registered at a DR-TB Centre of Southern India

Quantitative Study of Physical, Social, Psychological, and Environmental Challenges Faced by Patients With Drug-Resistant Tuberculosis.

Background This study chronicles the socioeconomic and emotional challenges experienced by patients suffering from drug-resistant tuberculosis (DR-TB) in India, the country with the highest tuberculosis (TB) burden globally. Current government measures under the National TB Elimination Programme (NTEP) that include widely available molecular diagnostic methods, well-defined DR-TB regimens, free drug distribution, treatment adherence strategies, etc. need to expand to cover socioeconomic and emotional aspects of the disease. Objective The objective of this study was to assess the effects of DR-TB and its treatment on the quality of life of patients in the psychological, social, environmental, and physical domains using validated scales. Method Conducted at a tertiary care center in Pune, this quantitative study utilized the World Health Organization Quality of Life (WHOQOL-BREF) questionnaire to objectively assess the quality of life of 64 DR-TB patients. The questionnaire was self-administered but assisted by the investigator to understand the meaning of the questions, and it covered four domains: psychological, social, environmental, and physical. Results The results indicated significant psychological distress, with the psychological domain scoring the lowest mean (33.41), followed by social (35.52), environmental (41.27), and physical domains (41.88). These findings underscore the profound impact of DR-TB on the mental health, social interactions, and overall well-being of these patients. Furthermore, substantial employment challenges, financial constraints, and fears of disease transmission were prevalent among patients, highlighting socioeconomic disparities. Conclusion The study emphasizes the necessity of holistic interventions that include psychological support, socioeconomic empowerment, and public health campaigns to improve the quality of life and treatment adherence for DR-TB patients. Future research should explore integrated care models that address both the clinical and psychosocial needs of patients. The insights from this study suggest a need for policy enhancements and resource allocation to better support this vulnerable population, ultimately aiming for more comprehensive and sustainable DR-TB management, thus focusing not only on the outcome but also on morbidity.

Age and gender in drug resistance tuberculosis: A cross-sectional case study at a national tuberculosis reference hospital in Nigeria

ObjectivesDrug resistance in tuberculosis (TB) is a very important public health threat that should not be ignored. Understanding the gender, age, and characteristics of individuals affected by TB (without HIV, diabetes, or hepatitis B complications), particularly in terms of drug resistance or susceptibility, is crucial for effective prevention and management strategies, as most studies focus on TB/HIV co-infection. MethodsA cross-sectional case study of age and gender was carried out in 140 individuals grouped into drug-resistant tuberculosis (DR-TB), drug-susceptible tuberculosis (DS-TB), and apparently healthy controls (AHCs). Data collection was through medical records and a structured questionnaire. Statistical analyses compared age, gender, and selected risk factors across the groups. ResultsThe mean age of the DR-TB group was 32 years (SD ≈ 2). A total of 80.0% were ≤40 years of age and four times more likely to have DR-TB; 55% were male, with 1.22 times more likelihood of DR-TB in males. The mean age of the DS-TB group was 34 years (SD ≈ 12); 66.7% were ≤40 years old. The odds ratio of DS-TB in males was 2.16. Only 10% of DR-TB enrolees had BCG scars compared with 65% AHCs. A high percentage of the DR-TB group reported handling raw meat (75%) and drinking unpasteurised milk (70%) compared with the DS-TB group. ConclusionsThe observed gender disparities and age-related factors, particularly among the DR-TB group, highlight the importance of considering age and gender factors in DR-TB prevention, diagnosis, and treatment. Our findings also highlight the need to bridge gaps in awareness as well as for the prevention of zoonotic TB and issues around effective BCG vaccination and coverage.

Innovative Bedaquiline-Based Delivery Systems for Multidrug-Resistant Tuberculosis Treatment

Abstract: The increasing incidence of multidrug-resistant tuberculosis (MDR-TB) is one of the most challenging tasks in tuberculosis treatment. Conventional TB treatment regimens have proven ineffective in treating MDR-TB, thus demanding the development of new drugs followed by delivery systems. Bedaquiline, a novel anti-TB drug, has been reported to inhibit the ATP synthase required for the growth and replication of TB bacteria. Bedaquiline is able to target the persistent or latent form of TB, which remains difficult to treat with conventional drugs. This makes bedaquiline an important drug in the fight against MDR-TB. The drug has been approved by the US FDA as well as European Medicines Agency and is now widely used as part of combination therapy for the treatment of MDR-TB. Bedaquiline and its ad-vanced drug delivery system play a key role in tackling MDR-TB, providing a much-needed boost to control and eventually eliminate the disease. However, the cost of the drug remains a concern, and efforts are underway to make bedaquiline more accessible and affordable to patients in resource-limited settings. Nevertheless, the development of bedaquiline nanofor-mulations represents a significant step forward in the fight against TB and offers hope to millions of patients across the globe.

A virulence-associated small RNA MTS1338 activates an ABC transporter CydC for rifampicin efflux in Mycobacterium tuberculosis.

The efficacy of the tuberculosis treatment is restricted by innate drug resistance of Mycobacterial tuberculosis and its ability to acquire resistance to all anti-tuberculosis drugs in clinical use. A profound understanding of bacterial ploys that decrease the effectiveness of drugs would identify new mechanisms for drug resistance, which would subsequently lead to the development of more potent TB therapies. In the current study, we identified a virulence-associated small RNA (sRNA) MTS1338-driven drug efflux mechanism in M. tuberculosis. The treatment of a frontline antitubercular drug rifampicin upregulated MTS1338 by >4-fold. Higher intrabacterial abundance of MTS1338 increased the growth rate of cells in rifampicin-treated conditions. This fact was attributed by the upregulation of an efflux protein CydC by MTS1338. Gel-shift assay identified a stable interaction of MTS1338 with the coding region of cydC mRNA thereby potentially stabilizing it at the posttranscriptional level. The drug efflux measurement assays revealed that cells with higher MTS1338 abundance accumulate less drug in the cells. This study identified a new regulatory mechanism of drug efflux controlled by an infection-induced sRNA in M. tuberculosis.

Multidrug-resistant tuberculosis clusters and transmission in Taiwan: a population-based cohort study.

Multidrug-resistant tuberculosis (MDR-TB) remains a challenge in the TB program of Taiwan, where 0.5% of new cases and 2.1% of previously treated cases were resistant to at least rifampin (RIF) and isoniazid (INH). Since >80% of our MDR-TB are new cases, genotyping of MDR Mycobacterium tuberculosis is implemented to facilitate contact investigation, cluster identification, and outbreak delineation. This is a population-based retrospective cohort study analyzing MDR-TB cases from 2019 to 2022. Whole genome sequencing (WGS) was performed using the Illumina MiSeq and analyzed using the TB Profiler. A single nucleotide polymorphism (SNP) threshold of ≤ 12 and phylogenetic methods were used to identify putative transmission clusters. An outbreak was confirmed using genomic data and epidemiologic links. Of the 297 MDR-TB cases, 246 (82.8%), 45 (15.2%), and 6 (2.0%) were simple MDR, extensively drug-resistant tuberculosis (pre-XDR-TB) and extensively drug-resistant tuberculosis (XDR-TB), respectively. The sublineage 2.2 modern Beijing was the predominant (48.8%) MDR-TB strain in Taiwan. Phylogenetic analysis identified 25.3% isolates in 20 clusters, with cluster sizes ranging from 2 to 13 isolates. Nevertheless, only 2 clusters, one household and one community, were confirmed as outbreaks. In this study, we found that males had a higher risk of MDR-TB transmission compared to females, and those infected with the sublineage 2.1-proto-Beijing genotype isolates were at a higher risk of transmission. Furthermore, 161 (54.2%) isolates harbored compensatory mutations in the rpoC and non-rifampicin resistant determinant region (non-RRDR) of the rpoB gene. MDR-TB strains containing rpoB S450L and other compensatory mutations concurrently were significantly associated with clusters, especially the proto-Beijing genotype strains with the compensatory mutation rpoC E750D or the modern Beijing genotype strains with rpoC D485Y/rpoC E1140D. Routine and continuous surveillance using WGS-based analysis is recommended to warn of risks and delineate transmission clusters of MDR-TB. We proposed the use of compensatory mutations as epidemiological markers of M. tuberculosis to interrupt putative MDR-TB transmission.

A network pharmacology-based approach to understand the mechanism of action of anti-mycobacterial activity of Acacia nilotica: a modelling and experimental study.

The rapid rise in drug-resistant tuberculosis poses a serious threat to public health and demands the discovery of new anti-mycobacterial agents. Medicinal plants are a proven potential source of bioactive compounds; however, identifying those responsible for the putative anti-mycobacterial action still remains a challenging task. In this study, we undertook a systematic network pharmacology approach to identify and evaluate anti-mycobacterial compounds from a traditional plant, Acacia nilotica, as a model system. The protein-protein interaction network revealed 17 key pathways in M. tuberculosis encompassing 40 unique druggable targets that are necessary for its growth and survival. The phytochemicals of A. nilotica were preferentially found to interfere with the cell division and cell wall biogenesis proteins, especially FtsZ and Mur. Notably, the compounds epigallocatechin, ellagic acid, chlorogenic acid, and D-pinitol were found to exhibit a potential polypharmacological effect against multiple proteins. Further, in vitro studies confirmed that the selected candidates, chlorogenic acid, and ellagic acid exhibited potent anti-mycobacterial activity (against M. smegmatis) with specific inhibition of purified M.tb FtsZ enzyme. Taken together, the present study demonstrates that network pharmacology combined with molecular docking can be utilized as an efficient approach to identify potential bioactive phytochemicals from natural products along with their mechanism of action. Hence, the compounds identified in this study can be potential lead candidates for developing novel anti-mycobacterial drugs, while the key proteins identified here can be potential drug targets.

Concomitant Rifampicin-Sensitive Pulmonary Tuberculosis With Pre-extremely Drug-Resistant Neuro-Tuberculosis in Child With Steroid-Resistant Nephrotic Syndrome.

Mixed tuberculosis occurs with multiple clonally distinct mycobacterium tuberculosis strains in an individual. We present a 12-year-old girl with steroid-resistant nephrotic syndrome and drug-sensitive pulmonary tuberculosis (Xpert MTB/Rif) and preextensively drug-resistant tuberculosis neuro-tuberculosis (Line Probe Assay). Mixed tuberculosis involving drug-susceptible and drug-resistant strains can hinder treatment. This case highlights the challenges in diagnosing mixed tuberculosis to ensure effective management.

Efficiency of Treatment of Tuberculosis Patients: Realities, Problems and Perspectives (Review)

An analysis of data from global experience and professional publications on modern treatment of tuberculosis patients and its effectiveness was carried out.The analysis of literary sources of recent years indicates an urgent problem regarding tuberculosis in Ukraine (especially in the conditions of martial law and the conduct of active hostilities). With early diagnosis and timely treatment, the number of patients decreases by 8 %.The effectiveness of the treatment of patients with pulmonary tuberculosis and the influence of various factors on it were evaluated. The effectiveness of treatment of newly diagnosed pulmonary tuberculosis in Ukraine does not exceed 70 %.An increase in the level of resistance of tuberculosis mycobacteria to anti-tuberculosis drugs was noted, and its treatment efficiency was not high. The effectiveness of treatment of such patients in Ukraine does not exceed 40—45 %. The inclusion of second-line drugs in the treatment regimen of patients with iso­niazid-­resistant tuberculosis increases the effectiveness of treatment by 11.8 %. The overall effectiveness of treatment of patients with multidrug-resistant tuberculosis (MDR-TB) in the world is 52 %, and only 10 % of patients are cured. The treatment of MRTB is three times longer (20 months) than that of the sensitive form and is significantly more expensive. Antimycobacterial drugs (AMBs) were used according to an individual regimen (18—20 months), then new AMBs were used (6 months), later versions of modified standardized short-term regimens (9 months). The BPaL regimen (bedaquiline, linezolid, pretomanide) was implemented for patients with multiple and extensively drug-resistant tuberculosis for 6 months (26 weeks or 182 doses), resulting in a cure rate of 90 % [35].The methods of optimizing the management of patients with pulmonary tuberculosis (including correction of treatment) in the conditions of martial law, which can be achieved by improving antimycobacterial and pathogenetic therapy, revealing new mechanisms and deepening the known regularities of the course of the disease, are evaluated.

Accessibility of Finding Tuberculosis Case Actively, Separate Safely and Treat Effectively (FAST) Strategy for Early Detection of Suspected and Symptomatic Tuberculosis Patients: A Hospital Based Quantitative Study

Introduction: Tuberculosis is a contagious disease which has always been a challenge over the course of human history. It is known to spread mostly from persons with undiagnosed and suspected tuberculosis cases. Diagnosing tuberculosis in an early stage with effective treatment is one of the best ways to reduce the burden of tuberculosis. Finding cases Actively, Separate safely and Treat effectively (FAST) Strategy in Nepal, is a rapid diagnostic tool for rapid tuberculosis case detection. Aims: To access tuberculosis case Actively, Separate safely and Treat effectively (FAST) strategy for suspected and symptomatic tuberculosis patients coming to the hospital for early case detection and also to identify patient’s health care behaviour, technical barrier during surveillance. Methods: An observational quantitative study of active cough surveillance was carried at an entry point of FAST corner of Nepalgunj Medical College Teaching Hospital, Banke from April 2023 to December 2023. Scrutinized data was obtained by purposive sampling method with sample size 128 from FAST corner. Results: Maximum cases belonged to the aged group 65 and above having lower middle to lower socioeconomic status. Most of them were from joint family with contact history of tuberculosis in 35 (27.3) % of total cases. Out of total cases, 72 (56.25) % were confirmed with tuberculosis. Among those confirmed tuberculosis cases, multi drug resistance TB was found in 6 (4.7) %. Uses of mask was found significant (P< 0.05) in our study although number of these health care behaviour were less appropriate. Pneumonia was a significant association 17 (P = 0.004) with tuberculosis patient. Insufficient volunteers, and limited Gene xpert machine were major barriers to implement FAST strategy screening in Hospital. Conclusion: FAST strategy is feasible tool in high tuberculosis burden healthcare settings in Nepal. However, the technical and behavioral factors should be managed to ensure an effective approach.

Implementation strategies for decentralized management of multidrug-resistant tuberculosis: insights from community health systems in Zambia

BackgroundDecentralized management approaches for multi-drug-resistant tuberculosis (MDR TB) have shown improved treatment outcomes in patients. However, challenges remain in the delivery of decentralized MDR TB services. Further, implementation strategies for effectively delivering the services in community health systems (CHSs) in low-resource settings have not been fully described, as most strategies are known and effective in high-income settings. Our research aimed to delineate the specific implementation strategies employed in managing MDR TB in Zambia.MethodsOur qualitative case study involved 112 in-depth interviews with a diverse group of participants, including healthcare workers, community health workers, patients, caregivers, and health managers in nine districts. We categorized implementation strategies using the Expert Recommendations for Implementing Change (ERIC) compilation and later grouped them into three CHS lenses: programmatic, relational, and collective action.ResultsThe programmatic lens comprised four implementation strategies: (1) changing infrastructure through refurbishing and expanding health facilities to accommodate management of MDR TB, (2) adapting and tailoring clinical and diagnostic services to the context through implementing tailored strategies, (3) training and educating health providers through ongoing training, and (4) using evaluative and iterative strategies to review program performance, which involved development and organization of quality monitoring systems, as well as audits. Relational lens strategies were (1) providing interactive assistance through offering local technical assistance in clinical expert committees and (2) providing support to clinicians through developing health worker and community health worker outreach teams. Finally, the main collective action lens strategy was engaging consumers; the discrete strategies were increasing demand using community networks and events and involving patients and family members.ConclusionThis study builds on the ERIC implementation strategies by stressing the need to fully consider interrelations or embeddedness of CHS strategies during implementation processes. For example, to work effectively, the programmatic lens strategies need to be supported by strategies that promote meaningful community engagement (the relational lens) and should be attuned to strategies that promote community mobilization (collective action lens).

The catalogue of Mycobacterium tuberculosis mutations associated with drug resistance to 12 drugs in China from a nationwide survey: a genomic analysis

WHO issued the first edition catalogue of Mycobacterium tuberculosis complex (MTBC) mutations associated with drug resistance in 2021. However, country-specific issues might lead to arising complex and additional drug-resistant mutations. We aimed to fully reflect the characteristics of drug resistance mutations in China. We analysed MTBC isolates from the nationwide drug-resistant tuberculosis surveillance with 70counties in 31provinces, municipalities, and autonomous regions in China. Three types of MYCOTB plates were used to perform drug susceptibility testing for 12antibiotics (rifampicin, isoniazid, ethambutol, levofloxacin, moxifloxacin, amikacin, kanamycin, ethionamide, clofazimine, linezolid, delamanid, and bedaquiline). Mutations were divided into five groups according to their odds ratios, positive predictive values, false discovery rate-corrected p values, and 95% CIs: (1) associated with resistance; (2) associated with resistance-interim; (3) uncertain significance; (4) not associated with resistance-interim; and (5) not associated with resistance. The Wilcoxon rank-sum and Kruskal-Wallis tests were used to quantify the association between mutations and minimum inhibitory concentrations (MICs). Our dataset was compared with the first edition of the WHO catalogue. We analysed 10 146MTBC isolates, of which 9071 (89·4%) isolates were included in the final analysis. 744(8·2%) isolates were resistant to rifampicin and 1339 (14·8%) to isoniazid. 208 (1·9%) of 11 065mutations were classified as associated with resistance or associated with resistance-interim. 33 (97·1%) of 34mutations in group 1and 92 (52·9%) of 174in group 2also appeared in groups 1or 2of the WHO catalogue. Of 81indel mutations in group 2, 15 (18·5%) were in the WHO catalogue. The newly discovered mutation gyrA_Ala288Asp was associated with levofloxacin resistance. MIC values for rifampicin, isoniazid, moxifloxacin, and levofloxacin corresponding to resistance mutations in group 1were significantly different (p<0·0001), and 12 high-level resistance mutations were detected. 61mutations in group 3occurred as solo in at least five phenotypically susceptible isolates, but with MIC values moderately higher than other susceptible isolates. Among 945phenotypically resistant but genotypically susceptible isolates, 433 (45·8%) were mutated for at least one efflux pump gene. Our analysis reflects the complexity of drug resistance mutations in China and suggests that indel mutations, efflux pump genes, protein structure, and MICs should be fully considered in the WHO catalogue, especially in countries with a high tuberculosis burden. National Key Research and Development Program of China and the Science and Technology Major Project of Tibetan Autonomous Region of China.

Identification of Chemical Scaffolds That Inhibit the Mycobacterium tuberculosis Respiratory Complex Succinate Dehydrogenase.

Drug-resistant Mycobacterium tuberculosis is a significant cause of infectious disease morbidity and mortality for which new antimicrobials are urgently needed. Inhibitors of mycobacterial respiratory energy metabolism have emerged as promising next-generation antimicrobials, but a number of targets remain unexplored. Succinate dehydrogenase (SDH), a focal point in mycobacterial central carbon metabolism and respiratory energy production, is required for growth and survival in M. tuberculosis under a number of conditions, highlighting the potential of inhibitors targeting mycobacterial SDH enzymes. To advance SDH as a novel drug target in M. tuberculosis, we utilized a combination of biochemical screening and in-silico deep learning technologies to identify multiple chemical scaffolds capable of inhibiting mycobacterial SDH activity. Antimicrobial susceptibility assays show that lead inhibitors are bacteriostatic agents with activity against wild-type and drug-resistant strains of M. tuberculosis. Mode of action studies on lead compounds demonstrate that the specific inhibition of SDH activity dysregulates mycobacterial metabolism and respiration and results in the secretion of intracellular succinate. Interaction assays demonstrate that the chemical inhibition of SDH activity potentiates the activity of other bioenergetic inhibitors and prevents the emergence of resistance to a variety of drugs. Overall, this study shows that SDH inhibitors are promising next-generation antimicrobials against M. tuberculosis.

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.

Exploring the therapeutic and prophylactic potential of bedaquiline in leprosy.

Leprosy remains a significant public health concern despite major strides in treatment and control efforts. The Global Leprosy Strategy 2021-2030 and the National Strategic Plan for Leprosy 2023-2027 majorly focus on facilitating action to reach the goal of zero leprosy. Exploration of new treatment regimens is emphasized as one of the verticals of the multipronged approach for reaching the aforementioned goals. This becomes particularly pertinent in the wake of growing evidence for resistance to the drugs currently being used in the management of leprosy. Repurposed molecules present a very good approach in this direction. The present review aims to explore the potential of bedaquiline, a drug used for multidrug-resistant tuberculosis, as a potential addition to the therapeutic armamentarium of leprosy. Through this narrative review, the authors attempt to look into the available proof of concept, clinical evidence, potential risks, and possible ways forward with bedaquiline in leprosy.

Tracking multidrug resistant tuberculosis: a 30-year analysis of global, regional, and national trends.

To provide valuable insights for targeted interventions and resource allocation, our analysis delved into the multifaceted burden, trends, risks, and projections of multi drug resistant tuberculosis (MDR-TB). This research employed data from the Global Burden of Disease (GBD) 2019 dataset, which used a comparative risk assessment to quantify the disease burden resulting from risk factors. Initially, this database was utilized to extract details concerning the disability-adjusted life years (DALYs), mortality, incidence, and the number of individuals afflicted by MDR-TB. Subsequently, regression analyses were conducted using the Joinpoint program to figure average annual percent change (AAPC) to ascertain the trend. Thirdly, the age-period-cohort model (APCM) was adopted to analyze evolutions in incidence and mortality. Finally, utilizing the Nordpred model within R software, we projected the incidence and mortality of MDR-TB from 2020 to 2030. MDR-TB remained a pressing global health concern in regions with lower socio-demographic indexes (SDI), where the AAPC in DALYs topped 7% from 1990 to 2019. In 2019, the cumulative DALYs attributed to MDR-TB tallied up to 4.2 million, with India, the Russian Federation, and China bearing the brunt. Notably, the incidence rates have shown a steadfast presence over the past decade, and a troubling forecast predicts an uptick in these areas from 2020 to 2030. Additionally, the risk of contracting MDR-TB grew with advancing age, manifesting most acutely among men aged 40+ in lower SDI regions. Strikingly, alcohol consumption had been identified as a significant contributor, surpassing the impacts of smoking and high fasting plasma glucose, leading to 0.7 million DALYs in 2019. A robust strategy is needed to end tuberculosis (TB) by 2030, especially in lower SDI areas.