The members of the PadR family of transcriptional regulators are important for cell survival in toxic environments and play an important role in detoxification, pathogenicity, and multi-drug resistance. Rv0047c of Mycobacterium tuberculosis H37Rv is annotated as a PadR family protein. We have characterized the stability and structure of Rv0047c. Rv0047c forms a stable dimer in solution. Its stability is characterized by a thermal melting transition temperature (Tm) of 55.3 °C. The crystal structure of Rv0047c was determined at a resolution of 3.15 Å. The structure indicates the biological unit to be a dimer with each monomer having a characteristic N-terminal winged-helix-turn-helix DNA binding domain and a C-terminal dimerization domain. The N-terminal domain is composed of four helices, α1, α2, α3, and α4 and two beta strands β1 and β2. The C-terminal dimerization domain (CTD) consists two long helices α6 and α7. The two domains are connected by helix α5. A short helical turn (helix αa, residue 89-92), leads to compaction of the α4-α5 loop. Rv0047c exhibits specificity in binding to an upstream region having an inverted repeat sequence. This binding is dependent upon Y18 and Y40 residue of Rv0047c, which are highly conserved among the PadR family. Overall, our results suggest a transcription regulatory role for Rv0047c, similar to other PadR family proteins.

To estimate the proportion of second-line anti-tuberculosis drug resistance among multidrug-resistant tuberculosis (MDR-TB) patients in Ethiopia.

A laboratory-based prospective cross-sectional study was conducted at the National Tuberculosis Reference Laboratory (NTRL), Ethiopia, from February 2022 to July 2024. Phenotypic drug susceptibility testing (pDST) assessed resistance to various second-line antituberculosis drugs. The collected data were entered into Microsoft Excel 2016 and imported into Statistical Package for Social Sciences (SPSS) version 23 for descriptive analysis.

Of 468 MDR-TB patients, 262 were new, and 206 were previously treated cases. Pre-extensively drug-resistant tuberculosis (pre-XDR-TB) was identified in four (1.52%) new cases and seven (3.40%) previously treated cases. Extensively drug-resistant tuberculosis (XDR-TB) was detected in three (1.15%) new cases and two (0.97%) previously treated cases. Overall, 11 (2.35%) cases were classified as pre-XDR-TB, and five (1.07%) as XDR-TB. Combined resistance to fluoroquinolones (FQs) and bedaquiline were detected in four cases (0.85%), comprising three new cases (1.15%) and one previously treated case (0.49%). Resistance to both FQs and linezolid was detected in a single previously treated case (0.49%) and acquired resistance to second-line drugs was identified in four cases.

Our study showed a prevalence of 2.35% for pre-XDR-TB and 1.07% for XDR-TB among MDR-TB cases, highlighting the importance of continuous surveillance and tailored treatment approaches to control the spread of drug-resistant TB (DR-TB) in Ethiopia. Future studies on MDR-TB surveillance should prioritize the integration of genomic surveillance into routine laboratory-based DR-TB monitoring systems to enhance early detection of resistance patterns, support targeted treatment strategies, and improve overall patient management efforts.

Background/Objectives: Compounds derived from pyrimido-diazepine have shown selective inhibition of the susceptible Mycobacterium tuberculosis strain H37Rv. However, there is a need for studies that evaluate the activity of these compounds against multidrug-resistant strains and clinical isolates. This study aims to evaluate the antitubercular potential of FTSD2 against drug-resistant strains of M. tuberculosis. Methods: The compound 4-(2,4-diamino-8-(4-methoxyphenyl)-8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepin-6-yl)-N-(2-(4-(dimethylamino)-6-(4-fluorophenyl)amino-1,3,5-triazin-2-yl)amino)ethyl)benzenesulfonamide (FTSD2) was tested against drug-resistant M. tuberculosis strains at minimal inhibitory and bactericidal concentrations (MIC and MBC). Kill curve assays were performed to assess bactericidal activity, and cytotoxicity was evaluated in human monocyte-derived macrophages and the RAW 264.7 murine macrophage cell line. Intracellular death assays, specifically macrophage infection assays, were also conducted to evaluate the effect of FTSD2 on intracellular M. tuberculosis growth. Results: FTSD2 inhibited the growth of drug-resistant M. tuberculosis at MIC and MBC values between 0.5 and 1 mg/L. Kill curve assays demonstrated concentration-dependent bactericidal activity. No cytotoxicity was observed in macrophages at concentrations below 64 mg/L. Additionally, FTSD2 significantly suppressed intracellular M. tuberculosis growth after 192 h. FTSD2 did not inhibit the growth of nontuberculous mycobacteria, including M. avium, M. abscessus, M. fortuitum, M. chelonae, and M. smegmatis at 50 mg/L. Conclusions: FTSD2 exhibits strong potential as a leading compound for the development of new antitubercular drugs, with selective activity against M. tuberculosis and minimal cytotoxic effects on macrophages. Further studies are needed to explore its mechanisms of action and therapeutic potential.

This perspective article, in recognition of World TB Day 2025, highlights the essential role that new tuberculosis (TB) vaccines play in meeting the World Health Organization's goal of ending TB by 2035. The article does not provide a comprehensive review of all vaccine candidates but emphasizes the urgent need for novel TB vaccines, given the limitations of the bacillus Calmette-Guérin vaccine and the increasing threat of drug-resistant strains. As TB continues to be a leading cause of global morbidity and mortality, with an estimated 10.8 million new cases in 2023, it is evident that current strategies are insufficient. Although advancements in vaccine research, including candidates such as M72/AS01E, show promise, the article underscores that achieving TB elimination requires vaccines that can prevent TB infection reactivation and transmission of drug-resistant strains. Overcoming scientific, logistical, and distribution challenges, particularly, in high-burden regions, will be critical to accelerating the availability of these vaccines. The article calls for intensified global collaboration and sustained investment in research to accelerate the development of novel vaccines, which are indispensable for reaching the World Health Organization's ambitious 2035 TB elimination targets.

The rise of multidrug-resistant tuberculosis (MDR-TB) remains a critical public health challenge, particularly in developing countries like Ethiopia. This systematic review and meta-analysis aimed to estimate the pooled prevalence of MDR-TB with co-infections and assess its effects among different co-infections in Ethiopia. The systematic review and meta-analysis were conducted from August to October 2024. The study adhered to PRISMA guidelines and utilized various academic databases including PubMed, Web of Science and Science Direct to identify relevant articles. To check for publication bias and small study effects, a funnel plot and Egger's test were employed. The statistical analysis was performed with R software version 4.4.1. From an original pool of 6,461 papers, 15 studies published between 2014 and 2024 were considered after applying certain inclusion and exclusion criteria. The analysis revealed an overall pooled prevalence of MDR-TB in the context of co-infections at 20% (95% CI: 14.0-26.0). Notably, the prevalence was higher among individuals with HIV co-infection at 23.2% (95% CI: 18.3-28.0), while it was lower in those with diabetes co-infection at 10% (95% CI: 3.0-17.3). The study found significant heterogeneity among the reported prevalence rates (I² = 94.93%, p < 0.001). These findings highlight the complex interplay between MDR-TB and other co-infections, posing significant challenges for clinical management and public health in Ethiopia. To enhance health outcomes and curb the spread of MDR-TB, government and public health authorities must implement targeted interventions, including monitoring and treatment programs in high-prevalence areas.

Tuberculosis (TB) is one of the leading causes of death due to infectious disease. It is a treatable disease; however, conventional treatment requires a lengthy treatment regimen with severe side effects, resulting in poor compliance among TB patients. Intermittent drug use, the non-compliance of patients, and prescription errors, among other factors, have led to the emergence of multidrug-resistant TB, while the mismanagement of multidrug-resistant TB (MDR-TB) has eventually led to the development of extensively drug-resistant tuberculosis (XDR-TB). Thus, there is an urgent need for new drug development, but due to the enormous expenses and time required (up to 20 years) for new drug research and development, new therapeutic approaches to TB are required. Host-directed therapies (HDT) could be a most attractive strategy, as they target the host defense processes instead of the microbe and thereby may prevent the alarming rise of MDR- and XDR-TB. This paper reviews the progress in HDT for the treatment of TB using repurposed drugs which have been investigated in clinical trials (completed or ongoing) and plant-derived natural products that are in clinical or preclinical trial stages. Additionally, this review describes the existing challenges to the development and future research directions in the implementation of HDT.

Drug-resistant TB (DR-TB) remains a major public health threat. In 2022, Uzbekistan reported 2,117 cases of DR-TB, with 69% tested for fluoroquinolone resistance. Limited information is available on the prevalence of resistance to bedaquiline, linezolid, and fluoroquinolone, which are key components of the all-oral treatment regimen for rifampicin-resistant TB in Uzbekistan.

A retrospective study was conducted using extensive programmatic data from 2019 to 2023 in Uzbekistan. We assessed second-line drug-resistant TB (SLDR-TB) rates using phenotypic drug susceptibility testing (pDST). Demographic and clinical characteristics associated with SLDR-TB were analysed using multivariable logistic regression models based on the Allen-Cady approach.

In total, 2,405 patients with TB who had undergone pDST were included (median age 40 years, 47% female). The overall SLDR-TB resistance rate was 24% (95% CI 22-26). Prevalence of resistance to bedaquiline, linezolid, moxifloxacin, levofloxacin, and amikacin were respectively 3.1%, 0.8%, 15%, 13%, and 12%. Risk factors for SLDR-TB were resistance to rifampicin and/or isoniazid, exposure to clofazimine, retreatment status, contact with drug-susceptible TB case or DR-TB case, and diabetes.

The high prevalence of SLDR-TB is of major concern, emphasising the need for baseline pDST in RR-TB treatment. Identified risk factors can aid early detection of at-risk individuals and inform clinical practice.

Background Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis, predominantly affecting the lungs (pulmonary TB) and is a significant public health challenge in India. The study aims to analyze demographic, radiological, and clinical subgroups of pulmonary TB cases, examine the relationship between smear acid-fast bacillus (AFB examination) and cartridge-based nucleic acid amplification test (CBNAAT), evaluate CBNAAT sensitivity for Mycobacterium tuberculosis (MTB) in new and previously treated patients, and determine the proportion of rifampicin resistance. Methods This hospital-based prospective study was conducted among patients diagnosed with pulmonary TB at the Respiratory Medicine Department of a Government Hospital over 16 months (August 2019 to December 2020). The study included 150 diagnosed TB cases (new and previously treated). Data collection encompassed demographic details, clinical symptoms, comorbidities, radiological findings (chest X-ray), and microbiological results (smear AFB examination, CBNAAT). Sputum samples were subjected to Ziehl-Neelsen staining and CBNAAT for MTB detection and rifampicin resistance testing. Statistical analysis was performed using IBM SPSS Statistics version 21.0 (IBM Corp., Armonk, NY, USA). Results Of the 150 patients, 69.3% were male, and 48% were aged 21-40 years. The majority had a BMI of 18.5-24.9 kg/m² (50%) and resided in urban areas (63.3%). Common symptoms included cough (95.3%), fever (80%), and weight loss (74%). Cavitary lesions on chest X-ray were observed in 84% of patients. Smear microscopy detected MTB in 72.7% of cases, while CBNAAT detected MTB in 94% of cases. CBNAAT sensitivity for smear-positive and smear-negative samples was 93.97% and 94.12%, respectively. Rifampicin resistance was found in 3% of new cases and 6% of previously treated cases. The sensitivity of smear microscopy was 77.33%, and the sensitivity of CBNAAT was 94%. Conclusion The study underscores the high burden of pulmonary TB and the utility of CBNAAT in detecting MTB and rifampicin resistance, particularly in smear-negative samples. The findings highlight the necessity of universal drug susceptibility testing (DST) for effective TB management and the importance of addressing drug resistance to improve treatment outcomes.

Tuberculosis (TB) is a chronic respiratory infectious disease that considerably jeopardizes human health, and there is no effective vaccine suitable for its prevention in the entire population.

To investigate the promotion of medication adherence and disease cognition in patients with drug-resistant (DR-)TB using detailed nursing management.

In total, 114 patients with DR-TB who were diagnosed and treated at our hospital between January 2019 and January 2023 were included in this study. Patients in the control group (n = 57) were managed with conventional nursing care, while those in the observation group (n = 57) were managed with detailed nursing care. Medication adherence, disease awareness scores, medication safety, and nursing satisfaction were compared between the two groups after the intervention.

The post-intervention medication compliance rate was 91.23% in the observation group and 75.44% in the control group, with the former being 15.79% higher than the latter (P < 0.05). There was no statistically significant difference in the disease awareness scores between the two groups before the intervention; the disease awareness scores of the observation group were significantly higher than those of the control group after the intervention (P < 0.05). The incidence of gastrointestinal reactions, joint swelling and pain, hearing loss, electrolyte disorders, and liver and kidney function abnormalities were lower in the observation group than those in the control group. The total nursing satisfaction of the observation group was higher than that of the control group (P < 0.05).

Implementation of detailed nursing management for patients with DR-TB can effectively improve medication adherence, enhance awareness of the disease, ensure safety of medication, and improve satisfaction with nursing care.

Bedaquiline (BDQ) is an effective drug currently used for multidrug-resistant or rifampicin-resistant TB (MDR/RR-TB) and pre-extensively drug-resistant TB (pre-XDR-TB) treatment. However, resistance to this new drug is emerging. We discussed the characteristics of the first patient in Ethiopia who acquired BDQ and fluoroquinolones (FQs) resistance during treatment follow-up.

In this case report, we present the case of a 28-year-old male pulmonary TB patient diagnosed with MDR-TB who is a resident of the Oromia Region of North Shewa, Mulona Sululta Woreda, Ethiopia. Sputum specimen was collected initially and for treatment monitoring using culture and for phenotypic drug susceptibility testing (DST) to first-line and second-line TB drugs. Initially, the patient was infected with a mycobacterial strain resistant to the first-line anti-TB drugs Rifampicin (RIF), Isoniazid (INH), and Pyrazinamide (PZA). Later, during treatment, he acquired additional drug resistance to ethambutol (EMB), ofloxacin (OFX), levofloxacin (LFX), moxifloxacin (MFX), and BDQ. The patient was tested with MTBDRplus and MTBDRsl to confirm the presence of resistance-conferring mutation and mutation was detected in rpoB, katG, and gyrA genes. Finally, the patient was registered as having extensively drug-resistant tuberculosis (XDR-TB) and immediately started an individualized treatment regimen.

This case report data has revealed the evolution of BDQ resistance during treatment with a BDQ-containing regimen in Ethiopia. Therefore, there is a need for DST to new second-line drugs to monitor and prevent the spread of DR-TB.

The rising prevalence and limited efficacy of treatments for pre-extensively drug-resistant tuberculosis (pre-XDR-TB) underscore an immediate need for innovative therapeutic options. A combination of host-directed therapy (HDT) and anti-TB treatment presents a viable alternative for pre-XDR-TB management. Sulfasalazine (SASP), by targeting the amino acid transport system xc (xCT), potentially reduces the intracellular Mycobacterium tuberculosis load and mitigates lung pathology, positioning it as a promising TB HDT agent. This study aims to assess the efficacy of SASP as a supplementary therapy for pre-XDR-TB.

A pilot study examined the safety and effectiveness of two 9-month short-course, all-oral regimens for pre-XDR-TB treatment: Bdq-regimen (consisting of Bdq, linezolid, cycloserine, clofazimine, and pyrazinamide) and SASP-regimen (comprising SASP, linezolid, cycloserine, clofazimine, and pyrazinamide). The primary endpoint was the incidence of unfavorable outcomes 12 months post-treatment.

Of the 44 participants enrolled, 43 were assessable 12 months post-treatment. Culture conversion rates stood at 73.2% by Month 2 and escalated to 95.1% by Month 6. Overall, 88.4% (38/43) of the participants exhibited favorable outcomes, 85.2% (19/23) for the Bdq-regimen and 93.8% (14/15) for the SASP-regimen. The SASP-regimen group recorded no deaths or treatment failures.

Both 9-month short-course, all-oral regimens manifested commendable primary efficacy in treating pre-XDR-TB patients. The SASP-regimen emerged as effective, safe, well-tolerated, and cost-effective.

The urgent need for new treatments for multidrug-resistant tuberculosis (MDR-TB) and pre-extensively drug-resistant tuberculosis (pre-XDR-TB) is evident. However, the classic randomized controlled trial (RCT) approach faces ethical and practical constraints, making alternative research designs and treatment strategies necessary, such as single-arm trials and host-directed therapies (HDTs).

Our study adopts a randomized withdrawal trial design for MDR-TB to maximize resource allocation and better mimic real-world conditions. Patients' treatment regimens are initially based on drug resistance profiles and patient's preference, and later, treatment-responsive cases are randomized to different treatment durations. Alongside, a single-arm trial is being conducted to evaluate the potential of sulfasalazine (SASP) as an HDT for pre-XDR-TB, as well as another short-course regimen without HDT for pre-XDR-TB. Both approaches account for the limitations in second-line anti-TB drug resistance testing in various regions.

Although our study designs may lack the internal validity commonly associated with RCTs, they offer advantages in external validity, feasibility, and ethical appropriateness. These designs align with real-world clinical settings and also open doors for exploring alternative treatments like SASP for tackling drug-resistant TB forms. Ultimately, our research aims to strike a balance between scientific rigor and practical utility, offering valuable insights into treating MDR-TB and pre-XDR-TB in a challenging global health landscape. In summary, our study employs innovative trial designs and treatment strategies to address the complexities of treating drug-resistant TB, fulfilling a critical gap between ideal clinical trials and the reality of constrained resources and ethical considerations.

Chictr.org.cn, ChiCTR2100045930. Registered on April 29, 2021.

Rising cases of drug resistance of mycobacterium species are one of the biggest concerns when the goal is to eradicate TB (Tuberculosis) from the world by the year 2030. A limited number of treatment options as MTB (Mycobacterium tuberculosis) is getting resistant to anti-mycobacterial drugs either due to a patient's non-compliance towards treatment regimen or if a patient is infected by drug-resistant species of MTB. This review aims to assess the effectiveness of pretomanid, a recently approved drug for the treatment of extensively drug-resistant TB. A thorough search of databases like PubMed, Cochrane library, CDC, Research Gate, and Google scholar was used in order to find case reports and clinical trials providing data on the efficacy of pretomanid in different drug regimens. According to research trials conducted, the drug appears to be efficacious, safe, and well-tolerable. Only headache was the most frequently observed adverse drug event, and a high dose-related increase in serum creatinine level was seen, which came to normal after the drug was discontinued.

Long, ineffective, and toxic regimens hinder the treatment of patients with multidrug-resistant tuberculosis (MDR-TB) and pre-extensive drug-resistant tuberculosis (pre-XDR-TB).

We conducted a multicenter cohort study to prospectively evaluate the safety and efficacy of three 9-month, all-oral, 5-drug regimens. Regimen A (bedaquiline [Bdq]+linezolid [Lzd]+moxifloxacin [Mfx]+cycloserine [Cs]+pyrazinamide [Pza]) and Regimen B (Lzd+Mfx+Cs+clofazimine [Cfz]+Pza) were used to treat MDR-TB patients (Groups A and B, respectively, assigned according to the patient's treatment preference), while Regimen C (Bdq+Lzd+Cs+Cfz+Pza) was used to treat pre-XDR-TB patients (Group C). The primary endpoint was the occurrence of an unfavorable outcome within 12 months of treatment completion, regardless of regimen.

A total of 104 patients (34 in Group A, 46 in Group B, and 24 in Group C), with a median age of 35.5 (29.0-54.0) years, were included in the analysis population. At 12 months after treatment completion, five patients were deemed non-assessable. Of the remaining 99 participants, seven (7.1%) had an unfavorable outcome (including two deaths from any cause, four with treatment failure, and one loss to follow-up) and 92 (92.9%) had a favorable outcome. Culture conversion was achieved in 82.5% (80/97) of participants at month 2 and in 97.9% (94/97) of participants at month 6. Adverse events (AEs) resulting in drug adjustment occurred in 69.2% (72/104) of participants, mainly due to Lzd and Pza use. A QT interval prolongation of ≥ 500 ms occurred in 5.8% (6/104) of participants.

The primary outcome of the three tailored, 9-month, all-oral, 5-drug regimens was satisfactory in the vast majority of MDR-TB and pre-XDR-TB patients, with manageable and reversible AEs.