Antituberculosis Therapy Research Articles

Molecular docking study of modified isoniazid compounds on mycolic acid synthase in the cell wall of mycobacterium tuberculosis

Using the isoniazid in antituberculosis therapy can lead to mutations in the KatG and inhA genes of Mycobacterium tuberculosis, resulting in the development of resistance and necessitating modifications to the isoniazid compound. This study aims to assess the potential and level of toxicity of modified compounds, namely 4-pyridine carboxylic acid, pyridine aldehyde, and methyl pyridine, on the mycolic acid receptor through a molecular docking approach. PyRx was employed for the docking process using a protocol with an exhaustiveness of 106 and a center grid box at X=42.424, Y=22.4321, and Z=46.6391. Additionally, the ProTox-II website was used to determine the toxicity level of the test compounds. The results obtained from this research consist of the respective affinity values of the test compounds: -6, -5.4, and -5.2 kcal/mol. The toxicity levels of the test compounds are as follows: class 5, class 4, and class 4. All test compounds interact with amino acids on the target protein, specifically with residue numbers Histidine (HIS A:8), Phenylalanine (PHE A:142) through hydrogen bonding, Leucine (LEU A:95) through pi-Sigma (π) bonding, and Valine (VAL A:12) through pi-Alkyl (π) bonding. In conclusion, the 4-pyridine carboxylic acid compound exhibits potential as a promising drug candidate but comes with a high level of toxicity

Perplexing paradoxical reactions: navigating the complexity of protracted tuberculosis meningitis—a case report

Tuberculous meningitis (TBM) has considerable mortality and morbidity, and it often presents therapeutic challenges when complicated by paradoxical reactions (PRs). Here, the clinical course of four cases of TBM patients complicated by PRs in a longitudinal TB cohort is described while also providing insights from the larger clinical cohort. Research flow cytometry, biomarker analysis, and drug concentrations were performed on available samples. All participants were initiated on standard antituberculosis therapy (ATT) and enrolled at the onset of PRs (PR group) or 2–4 months after the start of ATT (controls). The four TBM participants highlighted here presented with fevers, headaches, neurological deficits, and fatigue at the initial presentation. Upon diagnosis, all were initiated on rifampin, isoniazid, pyrazinamide, and ethambutol (RHZE) at standard doses and on corticosteroids. The median time to first PR was 37 days with recrudescence of initial TBM signs and symptoms at the time of PR. At the time of referral, all participants had low drug concentrations requiring dose optimization and regimen intensification as well as recrudescent flares upon corticosteroid taper, with one individual developing enlargement of tuberculoma 1 year following completion of ATT. Based on biomarkers and flow cytometry, PRs are characterized by elevated interferon-gamma and ferritin levels in the plasma compared to controls. In the TBM participants, T-cell activation with elevated levels of inflammatory biomarkers in the cerebrospinal fluid (CSF) was seen at the time of PR. These unique and highly detailed TBM cases provide insights into the pathogenesis of PRs, which may assist with future diagnostics and treatment.

Xpert MTB/RIF Ultra as a diagnostic tool for pleural tuberculosis: a study at Indian tertiary care centre.

Despite the advent of Xpert MTB/RIF, pleural tuberculosis (TB) diagnosis in pleural fluid is still difficult. Hence, we assessed the diagnostic efficacy of its advanced version, Xpert MTB/RIF Ultra for pleural TB diagnosis using pleural fluid as sample. Tuberculosis pleuritis (TBP) suspects (n=261) were enrolled in the study of which 29 were excluded. The remaining patients (n=232) were categorized into definite TBP (n=31), probable TBP (n=28), and non-TB controls (n=173) based on composite reference standard consisting of smear, culture, histopathology, and Xpert MTB/RIF as well as follow up/clinical response to anti-tuberculosis therapy. Among the TBP suspects, 59 were diagnosed as TBP patients. The sensitivity of Xpert MTB/RIF Ultra (52.5%) using pleural fluid for TBP diagnosis was higher than sensitivity obtained with smear (22.4%), culture (17.6%), and Xpert MTB/RIF (25%) alone, carried using either pleural fluid or pleural biopsy or both the samples. In cases of probable TBP, where none of the laboratory tests were positive, Xpert MTB/RIF Ultra use led to an increased diagnostic percentage of definite TBP from 52.5% to 69.4% Overall, the Xpert MTB/RIF Ultra showed promising results for a definitive diagnosis of TBP in pleural fluid samples.

Giant intracranial tuberculomas in children: An unexpected diagnosis and difficult management – About two cases and review of the literature

Background: Giant intracranial tuberculomas are rare space-occupying lesions in the brain parenchyma, with a diameter >2.5 cm. They can mimic gliomas, meningiomas, and metastases. Diagnosis of this disease can be difficult without histological evidence. Tuberculosis (TB) affects people of all ages but is a major health problem among children. Misdiagnosis is common, as many clinical and radiological features are non-specific. Case Description: Case 1: A 4-year-old child presented with intracranial hypertensive syndrome and Brave– Jackson seizures. Imaging showed a left temporoparietal lesion with intense peripheral ring enhancement after gadolinium injection, and attaching to the dura mater. Total surgical excision was performed, and histological analysis confirmed granulomatous TB. A month later, he presented to the emergency department with neurological deterioration. Magnetic resonance imaging revealed disseminated TB of the central nervous system, with tuberculomas in the brain stem. The child died after a month in intensive care. Case 2: An 11-year-old boy presented with a headache that had been progressively worsening for 7 months. Imaging revealed a right frontal process mimicking a high-grade glial tumor. The child underwent surgery with total excision of the tumor. After a few days, he developed tubercular miliaria and was put on anti-bacillary treatment. Conclusion: Treatment includes antituberculosis therapy combined with surgery. This article describes the value of surgery for giant intracranial tuberculomas in two children under our care, with a review of the literature. We believe that the results of surgery for giant intracranial tuberculomas in children are favorable.

Reevaluating Pediatric Osteomyelitis with Osteoarticular Tuberculosis: Addressing Diagnostic Delays and Improving Treatment Outcomes

Background: Pediatric osteoarticular tuberculosis (TB) remains a significant global health challenge, particularly in resource-limited settings, where delayed diagnosis and treatment frequently lead to severe long-term complications. Despite advancements in TB control, skeletal TB in children is often misdiagnosed due to its non-specific clinical presentation, contributing to poor outcomes such as joint deformities, growth disturbances, and chronic pain. The complexity of diagnosing osteoarticular TB is further exacerbated by the limited sensitivity of conventional diagnostic tools and the overlap with other musculoskeletal conditions. This study seeks to evaluate the impact of early detection and multidisciplinary management on treatment outcomes in pediatric patients with osteoarticular TB. Methods: A retrospective review was conducted at the Pediatric Orthopedics Department of the “Grigore Alexandrescu” Children’s Hospital in Romania from 2009 to 2023. Case data included clinical, imaging, and microbiological findings, and treatment outcomes in children aged 0–18 years diagnosed with tuberculous osteomyelitis. Results: The study identified varied clinical presentations, with delayed diagnosis often linked to misinterpretation of symptoms as non-TB infections. Multimodal diagnostic approaches combining imaging, microbiological testing, and histopathology improved diagnostic accuracy. Early surgical intervention alongside anti-TB therapy proved effective in reducing long-term complications. Conclusions: Timely, accurate diagnosis and multidisciplinary treatment are critical to improving outcomes in pediatric osteoarticular TB. Vaccination status and comprehensive diagnostic tools significantly influence disease progression and treatment success. The study underscores the need for enhanced screening and diagnostic methods to prevent delays in treatment.

Intestinal obstruction following antituberculosis therapy in a patient with pancreatic carcinoma and pulmonary tuberculosis: a case report

IntroductionIntestinal obstruction is a common complication in patients with advanced malignancies, often attributed to the disease itself or as a side effect of opioid analgesics used for pain management. However, the occurrence of intestinal obstruction following antituberculosis therapy is rare.Case presentationWe report a unique case of a 58-year-old Asian male diagnosed with stage IV pancreatic carcinoma and pulmonary tuberculosis. The patient was initiated on a regimen of ethambutol hydrochloride, pyrazinamide, rifampicin, and isoniazid tablets (II) for tuberculosis, alongside morphine for the management of severe cancer-related pain. Subsequently, he developed symptoms indicative of intestinal obstruction. Despite discontinuation of morphine, the patient’s symptoms persisted until he autonomously ceased all medications, leading to a rapid improvement in his condition. This unexpected resolution highlighted the antituberculosis drugs as the probable cause of his intestinal obstruction.ConclusionsThis case underscores the importance of considering antituberculosis drugs as a potential cause of intestinal obstruction, especially in patients who do not respond to conventional management strategies for drug-induced gastrointestinal side effects. It also emphasizes the need for heightened vigilance and monitoring when prescribing these medications to patients with advanced malignancies, to promptly identify and address rare but significant side effects.

Possibilities of Adding Pulmonary Surfactant to Comprehensive Therapy of Patients with Respiratory Tuberculosis: Results of a Prospective Comparative Study

The objective: to assess effectiveness and safety of the surfactant as part of comprehensive anti-tuberculosis therapy in pulmonary tuberculosis patients depending on the drug resistance pattern and HIV status.Subjects and Methods. 184 patients with pulmonary tuberculosis were enrolled in the study, of them 130 (70.7%) were men and 54 (29.3%) were women. All patients were randomized into Main Group (MG) and Control Group (CG). Surfactant therapy was added to comprehensive anti-tuberculosis therapy of the patients from Main Group. Additionally, each group was divided into subgroups based on HIV status.Results. The addition of surfactant therapy to comprehensive anti-tuberculosis therapy increases effectiveness of treatment improving such parameters as sputum conversion and cavity healing regardless of drug susceptibility pattern including patients with concomitant HIV infection. At the same time, the agent used for surfactant therapy demonstrated good tolerability.

Lentinan combined with docetaxel and nedaplatin in the treatment of pulmonary tuberculosis complicated by nonsmall cell lung cancer

Purpose: To investigate the efficacy and safety of lentinan combined with docetaxel and nedaplatin (DN) in the treatment of pulmonary tuberculosis complicated by non-small cell lung cancer (NSCLC). Methods: A total of 100 patients diagnosed with pulmonary tuberculosis combined with NSCLC in Ankang People's Hospital, Ankang, China were randomized equally into study and control groups. Control group received standard anti-tuberculosis therapy and intravenous chemotherapy regimen based on docetaxel (75 mg/m² on day 1) and nedaplatin (80 – 100 mg/m²), while the study group received, in addition, lentinan (given intravenously every two days). The patients received a total of 2 courses of treatment. Tumor response, survival, adverse reactions, quality of life score, and pulmonary function indices were compared before and after treatment. Results: The study group showed significantly higher total response rate than the control group (p < 0.05). Median overall survival and progression-free survival in the study group was significantly higher than in the control group (p < 0.05). Also, the study group showed significantly lower incidence of adverse reactions compared to control group (p < 0.05). Quality of life score, maximum voluntary ventilation (MVV) and peak expiratory flow (PEF) levels in the study group was significantly higher compared to control group (p < 0.05). Conclusion: Lentinan combination with DN chemotherapy regimen improves response rate, prolongs survival, reduces incidence of adverse reactions, improves quality of life and pulmonary function in patients with pulmonary tuberculosis complicated by NSCLC. These findings provide a new perspective for future studies on the application of lentinan in the treatment of pulmonary tuberculosis complicated by NSCLC.

Possibilities of Immunogenetic Methods in Testing the Activity of Tuberculosis Infection in Children

The objective: to test the TREC/KREC DNA levels in children with various manifestations of tuberculosis infection.Subjects and Methods. A prospective, cross-sectional study was conducted in 2022-2024. Observation Group consisted of 115 children aged 6 (5; 7) years, of them 25 were diagnosed with tuberculosis, 63 were diagnosed with latent tuberculosis infection, 27 were not infected with Mycobacterium tuberculosis (conditionally healthy). Results. Findings of the study were as follows: among children with LTBI and a positive response to TRA, only 18.2% had the high TREC DNA concentration which corresponded to the level in the children ill with tuberculosis (t = 0.971; p = 0.342), there was a direct relationship between the TREC DNA and KREC DNA levels in children with LTBI; in 21.2% of children the level was low and indicative of immunodeficiency. If the positive response to TRA persisted in children for two years or more, there was a decrease in the average TREC DNA level, which was statistically significant compared to that in children with TRA+ for less than 2 years. Taking into account the results obtained, the TREC DNA level in children with LTBI can be considered as an additional criterion to assess activity of tuberculosis infection and can be an evidence to justify preventive anti-tuberculosis therapy if studied further. We also found a direct correlation between the TREC and KREC DNA levels in children with LTBI, r = 0.48 (by Spearman). When the positive response to TRA persisted for more than two years, a statistically significant decrease in the TREC DNA level was noted versus the results in children with the first positive response to TRA (t = 2.965; p = 0.005).Conclusion. Taking into account the results obtained, the TREC DNA level in patients with various manifestations of tuberculosis infection can be considered as an additional criterion of infection activity, which will allow differentiated approach to preventive treatment being an important evidence to justify anti-tuberculosis therapy.

Liver Injury in People With HIV on Antituberculosis and/or Antiretroviral Therapy-Assessing Causality Using the Updated Roussel Uclaf Causality Assessment Method.

We compared performance of the Roussel Uclaf Causality Assessment Method (RUCAM) with multidisciplinary expert panel review in identifying a drug-induced liver injury (DILI) due to antituberculosis therapy (ATT) and/or antiretroviral therapy (ART). Cases were drawn from a prospective registry of hospitalised adults with suspected DILI due to ATT and/or ART in Cape Town, South Africa. Participants had to fulfil American Thoracic Society criteria for ATT interruption (alanine transaminase [ALT] ≥5 times upper limit of normal [ULN]/ALT ≥3 times [ULN] and symptomatic). Causality assessment by expert panel review served as reference standard. The panel ranked potentially implicated drugs as certain, probable, possible or unlikely causes guided by World Health Organization Uppsala Monitoring Centre criteria. The RUCAM was performed for each potentially implicated drug. We calculated sensitivity and specificity of the RUCAM in identifying a probable/certain drug cause for liver injury. We included 48 participants. All were people with HIV (PWH). Twenty-seven were on concomitant ART and ATT, with a median of six potentially hepatotoxic drugs per case. Sensitivity and specificity of the RUCAM in identifying a probable/certain drug cause of liver injury compared with expert panel review was 7% and 100% respectively. Implicated drugs (times ranked probable/certain by panel) were isoniazid (18/0), pyrazinamide (17/0), rifampicin (15/1), efavirenz (6/4) and lopinavir/ritonavir (1/0). PWH with liver injury received multiple potentially implicated drugs, which may increase liver injury risk and complicate causality assessment. Compared with expert panel review, the RUCAM had low sensitivity in detecting probable or certain drug causes of liver injury.

Spectrum of Ocular Tuberculosis in Tertiary Care Hospitals of Khyber Pakhtunkhwa Peshawar

Purpose: To describe the spectrum of ocular tuberculosis (TB), highlight the difficulty in diagnosis and treatment of such cases encountered in a tertiary care hospital of Peshawar, Pakistan. Study Design: Descriptive Case series. Place and Duration of Study: Khyber teaching hospital MTI Peshawar from Jan 2021 till July 2022. Methods: Eleven cases with Ocular tuberculosis are described. At presentation, complete history was taken and detailed examination was done including fundus examination and OCT macula. For diagnosis, a combination of Tuberculin skin test (TST) and Quantiferon-Gold was performed. On the basis of results of both tests Anti-TB treatment (ATT) was started and continued for an average of 9 months. Results: This study highlights the diverse ocular manifestations of TB in patients, even without a known history of systemic disease. Among 11 patients, 3 presented with panuveitis, 6 with posterior uveitis, and 2 with serpiginous-like choroidopathy with uveitis. Notably, only 2 had a known history of systemic TB. The patients were treated primarily with Anti-Tuberculosis Therapy (ATT) along with steroids or other adjunct therapies. Most cases showed improved vision and stable disease post-treatment, with visual acuity ranging from 6/24 to 6/6. However, two patients were lost to follow-up, leaving their outcomes unknown. Conclusion: In this case series, we explore different cases of Ocular Tuberculosis (OTB) seen at a busy hospital in Peshawar, Pakistan. There are variety of symptoms with which the patients present. The combined use of TST and Quantiferon-Gold proved an effective and affordable approach for diagnosis and timely initiation of ATT in ocular TB.

Poncet rheumatism secondary to ceco-appendicular tuberculosis in systemic lupus erythematosus

Background. Poncet’s rheumatism (RP) is an aseptic reactive arthritis secondary to active tuberculosis. Systemic lupus erythematosus (SLE) and tuberculosis are intricately related with an increase in the risk of tuberculosis in SLE. We present an original case of Poncet’s disease secondary to appendicular tuberculosis in patient with lupus disease. Case report. A 36-year-old female was followed in internal medicine for systemic lupus. In September 2023, she suffered from digestive complaints and polyarthritis. Infectious investigation and microbiologic study of joint fluid was negative. She had tenderness on pressure on the right iliac fossa. The computed tomography (CT) found an appendicular mucocele. She underwent laparotomy with right colectomy. Macroscopic aspect revealed tumorous lesion suggestive for malignancy. Histological study concluded to granulomatous inflammation with epithelioid and gigantocellular granulomas with anhist necrosis. Ceco-appendicular tuberculosis was retained. The patient received the anti-tuberculosis therapy with good progress. Conclusions. Early recognition of atypical location of tuberculosis leads to initiate appropriate treatment especially in immune compromise statue patient.

Epidemiological characteristics, diagnosis and treatment effect of rifampicin-resistant pulmonary tuberculosis (RR-PTB) in Guizhou Province

BackgroundRifampicin-resistant pulmonary tuberculosis (RR-PTB) presents a significant threat to global public health security. China bears a substantial burden of RR-PTB cases globally, with Guizhou Province experiencing particularly alarming trends, marked by a continual increase in patient numbers. Understanding the population characteristics and treatment modalities for RR-PTB is crucial for mitigating morbidity and mortality associated with this disease.MethodsWe gathered epidemiological, diagnostic, and treatment data of all RR-PTB cases recorded in Guizhou Province from January 1, 2017 to December 31, 2023. Utilizing composition ratios as the analytical metric, we employed Chi-square tests to examine the spatiotemporal distribution patterns of RR-PTB patients and the evolving trends among different patient classifications over the study period.ResultsIn our study, 3396 cases of RR-PTB were analyzed, with an average age of 45 years. The number of RR-PTB patients rose significantly from 176 in 2017 to 960 in 2023, peaking notably among individuals aged 23–28 and 44–54, with a rising proportion in the 51–80 age group (P < 0.001). Since 2021, there has been a notable increase in the proportion of female patients. While individuals of Han ethnic group comprised the largest group, their proportion decreased over time (P < 0.001). Conversely, the Miao ethnicity showed an increasing trend (P < 0.05). The majority of patients were farmers, with their proportion showing an upward trajectory (P < 0.001), while students represented 4.33% of the cases. Geographically, most patients were registered in Guiyang and Zunyi, with a declining trend (P < 0.001), yet household addresses primarily clustered in Bijie, Tongren, and Zunyi. The proportion of floating population patients gradually decreased, alongside an increase in newly treated patients and those without prior anti-tuberculosis therapy. Additionally, there was a notable rise in molecular biological diagnostic drug sensitivity (real-time PCR and melting curve analysis) (P < 0.001). However, the cure rate declined, coupled with an increasing proportion of RR-PTB patients lost to follow-up and untreated (P < 0.05).ConclusionsEnhanced surveillance is crucial for detecting tuberculosis patients aged 23–28 and 44–54 years. The distribution of cases varies among nationalities and occupations, potentially influenced by cultural and environmental factors. Regional patterns in RR-PTB incidence suggest tailored prevention and control strategies are necessary. Despite molecular tests advances, challenges persist with low cure rates and high loss to follow-up. Strengthening long-term management, resource allocation, and social support systems for RR-PTB patients is essential.

A novel method for characterizing cell-cell interactions at single-cell resolution reveals unique signatures in blood T cell-monocyte complexes during infection.

Communication between immune cells through direct contact is a critical feature of immune responses. Here, we developed a novel high-throughput method to study the transcriptome and adaptive immune receptor repertoire of single cells forming complexes without needing bioinformatic deconvolution. We found that T cells and monocytes forming complexes in blood during active tuberculosis (TB) and dengue hold unique transcriptomic signatures indicative of TCR/MCH-II immune synapses. Additionally, T cells in complexes showed enrichment for effector phenotypes, imaging and transcriptomic features of active TCR signaling, and increased immune activity at diagnosis compared to after anti-TB therapy. We also found evidence for bidirectional RNA exchange between T cells and monocytes, since complexes were markedly enriched for "dual-expressing" cells (i.e., co-expressing T cell and monocyte genes). Thus, studying immune cell complexes at a single-cell resolution offers novel perspectives on immune synaptic interactions occurring in blood during infection.

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.

Successful Management of Complex Intestinal Tuberculosis with Ileal Perforation: A Case Report

Background: Intestinal tuberculosis (ITB) with ileal perforation represents a formidable challenge in the realm of extrapulmonary tuberculosis. This case report underscores the complexities inherent in managing such cases, highlighting the critical need for a multidisciplinary approach that integrates pharmacological and surgical interventions. Case presentation: A 57-year-old male presented with a history of both pulmonary and intestinal tuberculosis, complicated by ileal perforation. He had previously undergone a six-month course of anti-tuberculosis treatment and a laparotomy for ileal perforation repair. The patient's current presentation included abdominal pain, nausea, and vomiting, indicative of obstructive ileus. Diagnostic assessments revealed elevated inflammatory markers and imaging confirmed partial obstructive ileus and active pulmonary tuberculosis. The patient was managed with extended anti-tuberculosis therapy and intravenous antibiotics, resulting in significant clinical improvement and enhanced quality of life. Conclusion: This case report emphasizes the importance of early detection, comprehensive assessment, and individualized treatment plans in managing complex ITB cases. The successful outcome achieved in this case underscores the efficacy of a multidisciplinary approach that combines pharmacological and surgical interventions.

Computational Exploration of Isatin Derivatives for InhA Inhibition in Tuberculosis: Molecular Docking, MD Simulations and ADMET Insights.

Anti-tubercular drug discovery is a critical research area aimed at addressing the global health burden imposed by Mycobacterium tuberculosis. Nowadays, computational techniques have increased the likelihood of drug development compared to traditional, labor-intensive, and time-consuming drug design approaches. The pivotal goal of drug design is to identify compounds capable of selectively targeting protein, thereby disrupting its enzymatic activity. InhA, or NADH-dependent enoyl-acyl carrier protein reductase, stands at the forefront of targeted approaches in the battle against TB. Isatin derivatives have garnered interest for their diverse pharmacological activities. To identify novel isatin derivatives that could serve as potential chemical templates for anti-TB drug discovery by targeting InhA. The present work utilized various computational approaches, including molecular docking, binding free energy calculations, and conformational alignment studies to investigate the binding mode and interactions of carefully selected dataset of 88 isatin derivatives within InhA active site. Study also employed MD simulations of the most promising molecule to check the stability of the protein-ligand complex and in-silico ADMET profiling of the top compounds to predict their pharmacokinetic and toxicity properties. Results provided insights into the structural features contributing to InhA inhibition, assessing overall drug-like characteristics of isatin derivatives and identified compound 48 (BA= -10.4 kcal mol-1 ) with potential for further optimization. MD simulation analysis revealed that compound 48 binds firmly within the InhA protein, exhibiting minimal conformational fluctuations and enhanced stability. Considering the aforementioned, isatin derivatives represents a novel framework for creating targeted InhA inhibitors during anti-TB therapy. However, experimental validations and in-depth analyses are crucial to confirm efficacy and safety of these derivatives as potential InhA inhibitors for TB treatment.

Successful Management of Miliary Tuberculosis with Concomitant Anemia: A Case Report

Background: Miliary tuberculosis (TB) is a disseminated and potentially fatal form of TB characterized by the hematogenous spread of Mycobacterium tuberculosis, often complicated by anemia of chronic disease. The diagnosis and management of miliary TB, particularly in conjunction with anemia, can be challenging, especially in resource-limited settings. Case presentation: We report the case of a 20-year-old male from a remote region in Eastern Halmahera, Indonesia, who presented with progressive shortness of breath, productive cough, night sweats, unintentional weight loss, and generalized weakness. Clinical examination revealed signs of anemia and respiratory distress. Laboratory investigations confirmed microcytic hypochromic anemia and a positive GeneXpert MTB/RIF test. Chest radiography demonstrated diffuse miliary nodules, consolidation, and cavitation, establishing the diagnosis of miliary TB with concomitant anemia. The patient received a standard six-month anti-tuberculosis therapy regimen, along with supportive care and targeted treatment for anemia and associated symptoms. The patient demonstrated significant clinical and hematological improvement, leading to discharge after 11 days of hospitalization. Follow-up assessments confirmed continued progress and the absence of complications. Conclusion: This case underscores the critical importance of maintaining a high index of suspicion for miliary TB in patients presenting with respiratory and constitutional symptoms, even in the absence of traditional risk factors. The presence of anemia can further complicate the clinical picture. Prompt diagnosis through a combination of clinical assessment, laboratory investigations, and imaging studies, followed by the immediate initiation of appropriate treatment, including the management of anemia, is paramount for achieving favorable outcomes in patients with miliary TB. The case also emphasizes the necessity for comprehensive care and follow-up to ensure sustained recovery and prevent relapse.

Structure and inhibition mechanisms of Mycobacterium tuberculosis essential transporter efflux protein A.

A broad chemical genetics screen in Mycobacterium tuberculosis (Mtb) to identify inhibitors of established or previously untapped targets for therapeutic development yielded compounds (BRD-8000.3 and BRD-9327) that inhibit the essential efflux pump EfpA. To understand the mechanisms of inhibition by these compounds, we determined the structures of EfpA with inhibitors bound at 2.7 -3.4 Å resolution. Our structures reveal different mechanisms of inhibition for the two inhibitors. BRD-8000.3 binds in a tunnel making contact with the lipid bilayer and extending toward the central cavity to displace the fatty acid chain of a lipid molecule bound in the apo structure, suggesting its blocking of an access route for a natural lipidic substrate, in contrast to its uncompetitive mechanism for the small molecule substrate ethidium bromide which likely enters through an alternative tunnel. Meanwhile, BRD-9327 binds in the outer vestibule without complete blockade of the substrate path to the outside, suggesting its possible inhibition of the dynamical motion necessary for "alternate access" to the two different sides of the membrane, as is characteristic of major facilitator superfamily (MFS) transporters. Both inhibitors may have a role in inhibiting the "alternate access" mechanism that could account for the uncompetitive nature of their efflux of some substrates. Our results explain the basis of the synergy of these inhibitors and their potential for combination in a multi drug strategy for anti-tuberculosis therapy. They also potentially point to a possible function for this essential efflux pump as a lipid transporter. The structures provide a foundation for rational modification of these inhibitors to increase potency.

Symptomatic bradycardia in tuberculosis-related giant bullae (vanishing lung syndrome): A case report

Rationale: Vanishing lung syndrome is rare and can be associated with a history of smoking and marijuana use. The occurrence of giant bullae can also be linked to infections, particularly tuberculosis in tropical countries. Patient concerns: A 26-year-old male complained of weakness, severe vomiting, and reduced breathlessness when lying on the left side. He had a history of pulmonary tuberculosis two years ago. Diagnosis: Symptomatic bradycardia in tuberculosis-related giant bullae. Interventions: The patient was recommended to undergo an elective bullectomy, but he decided not to proceed with the procedure. Atropine sulfate was administered to alleviate symptoms of bradycardia, while a standardized anti-tuberculosis regimen were started for the next six months. Outcomes: Following 7 days of intensive care treatment involving antituberculosis medications and atropine sulfate, the patient achieved hemodynamic stability, opting against bullectomy despite residual symptoms of dyspnea. Subsequent six months of antituberculosis therapy notably alleviated symptoms without requiring bullectomy. Lessons: Increasing intrathoracic pressure can also be caused mechanically by giant bullae. Cardiac symptoms in vanishing lung syndrome are reversible and can be alleviated once the underlying cause is addressed. In this case, symptomatic bradycardia was reduced only with tuberculosis treatment without bullectomy intervention.