Mycobacterium tuberculosis inhibitors: an updated patent review (2021-present).

INTRODUCTION: Tuberculosis (TB) remains a major global health issue, causing around 10 million new cases and 1.3 million deaths in 2022. The challenge is compounded by multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB strains, and co-infection with HIV. AREAS COVERED: The present review examines significant patent literature on TB chemotherapeutics from September 2021 to the present using the following databases, reaxys, google patent and espacenet. Only patents reporting compounds with a minimum inhibitory concentration (MIC) on whole Mycobacterium tuberculosis cells of ≤5 µM were selected for review. EXPERT OPINION: The fight against TB is advancing with the development of promising new compounds due to the challenge of drug-resistant strains. Notable among those reviewed in this paper are the benzothiazinones, showing high efficacy against both drug-sensitive and resistant TB strains. Additionally, Q203 analogues, demonstrate strong antitubercular activity, good microsomal stability, and favorable safety profiles. Finally, LysRS inhibitors also show significant promise in vivo models. These advancements underscore the importance of novel targets and innovative strategies in developing effective, resistance-resistant TB treatments.

Pharmacokinetics-pharmacodynamics of first-line antitubercular drugs: a comparative study in tuberculosis patients with and without concomitant diabetes mellitus.

PURPOSE: To observe the variability in the plasma concentrations and pharmacokinetic-pharmacodynamic (PK-PD) profiles of first-line antitubercular drugs in pulmonary tuberculosis (TB) patients with and without diabetes mellitus (DM). METHODS: Newly diagnosed pulmonary TB patients aged 18-60 years with or without DM were included in the study. Group I (n = 20) included patients with TB, whereas group II (n = 20) included patients with both TB and DM. After 2 weeks of therapy, plasma concentrations and other PK-PD parameters were determined. Improvements in clinical features, X-ray findings, sputum conversion, and adverse drug reactions (ADRs) were assessed after 2 months of therapy. RESULTS: Isoniazid displayed non-significantly higher plasma concentrations in diabetic patients, along with a significantly (P < 0.05) longer elimination half-life (t1/2). Rifampicin plasma concentrations at 4, 8, and 12 h were significantly (P < 0.05) lower, and it displayed significantly (P < 0.05) lower area under the curve (AUC0-12 and AUC0-∞), shorter t1/2, higher clearance (Cl), and a lower AUC0-∞/MIC ratio in diabetic patients. Pyrazinamide and ethambutol showed non-significantly higher plasma concentrations, AUC0-12, AUC0-∞, and t1/2 in diabetic patients. The improvements in clinical features, X-ray findings, sputum conversion, and ADRs were comparable in both groups. CONCLUSIONS: The presence of DM in TB patients affects the PK-PD parameters of isoniazid, rifampicin, pyrazinamide, and ethambutol variably in the Indian population. Studies with a larger number of patients are required to further elucidate the role of DM on the PK-PD profile of first-line antitubercular drugs and treatment outcomes in TB patients with concomitant DM. TRIAL REGISTRATION: CTRI/2021/08/035578 dated 11/08/2021.

Pulmonary infection by Mycobacterium riyadhense: first case report in United Arab Emirates.

Mycobacterium riyadhense is an emerging slowly growing species that belongs to the group of nontuberculous mycobacteria (NTM) with approximately 20 cases reported worldwide. We highlight the first case of pulmonary infection by Mycobacterium riyadhense in United Arab Emirates (UAE). A 44-year-old female presented with chronic productive cough; a bronchial breathing pattern was appreciated on auscultation of her right upper lung. She was treated multiple times with allergic medications and antibiotics. Thorough investigations revealed Mycobacterium riyadhense and antitubercular drugs were started, eventually she was cured, however she had multiple relapses later. This case report holds a significant potential to make considerable contribution to the diagnosis of NTM, primarily because it presents the first documented case in UAE, as well as insights on how to address possible similar cases in the future.

Factors associated with treatment adherence among pulmonary tuberculosis patients in New Delhi.

BACKGROUND: TB is treated with a six-month course of four antimicrobial drugs, and nearly all cases of TB can be cured if the medications are given and taken correctly. Due to its prolong treatment plans, there can be reasons associated with non-adherence to treatment by TB patients. Hence, the present study aimed to explore the factors associated with medication adherence among TB patients. METHOD: A cross-sectional descriptive survey was conducted among adult pulmonary tuberculosis patients enrolled under RNTCP (now NTEP) in New Delhi among 27 functional RNTCP districts. Around 200 TB patients who are enrolled in the Nikshay App and are also on treatment were considered. A structured questionnaire was prepared for the interview guide. Analysis was done using bivariate analysis, chi-square tests, and Fisher's exact tests. RESULTS: Among the total participants, 173 (86.5%) were adherent and the remaining 27 (13.5%) participants were non-adherent. The majority of the participants (91%) said they were able to follow the routine to the DOTS center, and 9% said they find it difficult to report to the DOTS center as per their schedule. Only 12.35% of non-adherent participants were seen among those who get regular reminders from their families to take medicines, as compared to 18.42% among those who did not get regular reminders from their families. More than one-fourth of the participants (25.9%) who report not getting necessary motivation from healthcare providers were non-adherent. Motivation by healthcare workers to follow drug schedules was found statistically significant to treatment compliance with a P-value of 0.0422. CONCLUSION: TB is a curable disease; this belief has turned out to be a motivational factor for patients suffering from this disease. Studies have shown that faith in the efficacy of treatment helps adherence to TB treatment while other studies describe how patient adherence was adversely affected by the belief that TB is incurable or the treatment is inefficient or that alternative treatment such as traditional medicine is better.

Antitubercular drug-induced lichen planus: A case study with a mini literature review.

Introduction: Drug-induced lichen planus is a cutaneous adverse effect that manifests as a systemic eruption of flat-topped, erythematous, or violaceous papules resembling lichen planus on the trunk and extremities. Although antitubercular therapy has been linked to cutaneous hypersensitivity reactions, the literature on such cases is scarce. Here, we present a case to contribute to this field, reporting on its presentation and management, and reviewing previous case studies. Case Report: Our patient, a 63-year-old male, presented with black pigmented patches on the skin, having been diagnosed with pulmonary tuberculosis and on antitubercular therapy for the past two months. A diagnosis of ATT-induced lichen planus was made, and all ATT was stopped. The patient was treated with antihistamines, apremilast, tacrolimus, and corticosteroids, and rechallenge of each drug was performed consecutively. No new lesions appeared after rechallenge with isoniazid and rifampicin. However, ethambutol was not reintroduced due to strong suspicion, by exclusion, that it was the offending agent, whereas on rechallenge with isoniazid and rifampicin, the patient's skin lesions gradually improved with eventual resolution of hyperpigmentation. Discussion and Conclusion: Lichenoid drug eruptions are characterized by type IV hypersensitivity reactions, and rechallenge is required to ensure safer treatment since the risk of disseminated and multi-drug-resistant tuberculosis increases with the cessation of antitubercular therapy.

Utility of Liver Biopsy in the Diagnosis and Management of Possible Drug-Induced Liver Injury in Patients Receiving Antituberculosis Therapy: A Retrospective Study.

BACKGROUND: Drug-induced liver injury (DILI) secondary to ATT treatment (TB-DILI) is reported in 2-28% of patients. We present here a series of clinical cases of suspected DILI arising during antituberculosis treatment, studied with the aid of liver biopsy. METHODS: this was a retrospective descriptive study including 10 tuberculosis patients who underwent liver biopsy for suspected TB-DILI at the "Lazzaro Spallanzani" Institute from 2017 to 2022. RESULTS: Ten patients who underwent LB were extracted from the database and included in the retrospective study cohort. According to the clinical classification, eight patients had hepatocellular liver injury, one patient had cholestatic injury, and another had mixed-type injury. Histopathological diagnosis revealed liver damage due to DILI in 5/10 (50%) cases. In one case, liver biopsy showed necrotizing granulomatous hepatitis. CONCLUSIONS: Severe and persistent elevation of hepatic transaminases, hepatic cholestasis despite discontinuation of therapy, and other suspected hepatic conditions are indications for liver biopsy, which remains a valuable tool in the evaluation of selected tuberculosis patients with suspected DILI for many reasons. However, the decision to perform a liver biopsy should be based on clinical judgment, considering the benefits and risks of the procedure.

In vitro bioevaluation and docking study of dihydrosphingosine and ethambutol analogues against sensitive and multi-drug resistant Mycobacterium tuberculosis.

Tuberculosis remains a major public health problem and one of the top ten causes of death worldwide. The alarming increase in multidrug-resistant and extensively resistant variants (MDR, pre-XDR, and XDR) makes the disease more difficult to treat and control. New drugs that act against MDR/XDR strains are needed for programs to contain this major epidemic. The present study aimed to evaluate new compounds related to dihydro-sphingosine and ethambutol against sensitive and pre-XDR Mycobacterium strains, as well as to characterize the pharmacological activity through in vitro and in silico approaches in mmpL3 protein. Of the 48 compounds analyzed, 11 demonstrated good to moderate activity on sensitive and MDR Mycobacterium tuberculosis (Mtb), with a Minimum Inhibitory Concentration (MIC) ranging from 1.5 to 8 µM. They presented 2 to 14 times greater potency of activity when compared to ethambutol in pre-XDR strain, and demonstrated a selectivity index varying between 2.21 and 82.17. The substance 12b when combined with rifampicin, showed a synergistic effect (FICI = 0.5) on sensitive and MDR Mtb. It has also been shown to have a concentration-dependent intracellular bactericidal effect, and a time-dependent bactericidal effect in M. smegmatis and pre-XDR M. tuberculosis. The binding mode of the compounds in its cavity was identified through molecular docking and using a predicted structural model of mmpL3. Finally, we observed by transmission electron microscopy the induction of damage to the cell wall integrity of M. tuberculosis treated with the substance 12b. With these findings, we demonstrate the potential of a 2-aminoalkanol derivative to be a prototype substance and candidate for further optimization of molecular structure and anti-tubercular activity in preclinical studies.

Maternal Tuberculosis Leading to Congenital Tuberculosis: A Case Report.

In India, tuberculosis (TB) is a severe public health concern. We report a case of a 45-day male baby who had respiratory distress and fever, whose mother was diagnosed with pulmonary TB infection prior to delivery which was confirmed by a positive Cartridge-Based Nucleic Amplification Test (CBNAAT) from the sputum and was on antitubercular therapy (ATT). Due to the symptoms, signs, and maternal TB history, congenital TB was strongly suspected. A positive CBNAAT result from the gastric lavage further supported this suspicion. This case emphasizes the value of obtaining details on the mother's TB history to aid in the early diagnosis of congenital TB and expedite the treatment and prognosis.

Determinants of adverse reactions to first-line antitubercular medicines: a prospective cohort study.

BACKGROUND: The success of tuberculosis treatment relies on patients adhering to their medication regimen consistently. However, adherence levels tend to decrease among patients who experience adverse drug reactions to antitubercular medications, leading to suboptimal treatment outcomes. Hence, this study aimed to examine the types, incidence rates, and severity of adverse reactions caused by first-line antitubercular drugs. Additionally, it aimed to identify factors associated with the development of these reactions. By doing so, the study aimed to facilitate the provision of personalized and effective treatment to patients, ultimately improving treatment outcomes. METHODS: Newly diagnosed patients with active tuberculosis were monitored from the start of their treatment until the completion of therapy. Any adverse reactions to anti-TB drugs that they encountered were carefully recorded. The collected data were analyzed using appropriate statistical methods such as analysis of variance, Chi-squared test, Fisher's exact test, and independent t-tests. Logistic regression was employed to assess the association between adverse drug reactions and various socio-demographic and clinical factors of the patients, using odds ratios as a measure of association. RESULTS: Among the 378 patients included in the study, 181 individuals (47.9%) reported experiencing at least one adverse drug reaction, with an incidence rate of 1.75 events per 100-person months. The majority of these reactions occurred during the intensive phase of treatment. The gastrointestinal tract was the most commonly affected system, followed by the nervous system and skin. Patients aged over 45 years (OR = 1.55, 95% CI 1.01-2.39, p = 0.046) and those with extrapulmonary tuberculosis (OR = 2.41, 95% CI 1.03-5.64) were more likely to develop gastrointestinal reactions. Female gender was a significant predictor of both skin (OR = 1.78, 95% CI 1.05-3.02, p = 0.032) and nervous system (OR = 1.65, 95% CI 1.07-2.55, p = 0.024) reactions. Additionally, alcohol use and HIV infection were identified as independent predictors of adverse drug reactions affecting all three systems. CONCLUSION: Significant risk factors for developing antitubercular drug adverse reactions include alcohol consumption, cigarette smoking, being HIV positive, female gender and extrapulmonary tuberculosis.

Effects of the Modified Antitubercular Treatment Regimen on Renal Function in Patients With Chronic Kidney Disease and Pulmonary Tuberculosis: An Observational Study.

INTRODUCTION: Chronic kidney disease (CKD) increases an individual's vulnerability to infections like tuberculosis. Doses of pyrazinamide and ethambutol are modified to treat such individuals. Additionally, the renal function tends to decline with advancing age. Therefore, it is crucial to study the effect of antitubercular drugs on renal function in young and elderly patients. The primary objective of this study was to determine the change in serum creatinine levels at six months from baseline in two study groups that included patients aged ≤50 and >50 years. The secondary objective was to determine changes in estimated glomerular filtration rate (eGFR) and BMI six months from baseline. METHODS: We recruited 40 patients with CKD and pulmonary tuberculosis from Srirama Chandra Bhanja (SCB) Medical College and Hospital, India. Each participant received the modified doses of antitubercular drugs. Their serum creatinine, eGFR, and BMI were assessed at baseline, two and six months. Participants had a mean age of 50.93±9.83 years. RESULTS: The median changes in serum creatinine and eGFR values from baseline were -0.19 and -0.23 mg/dl and 4.16 and 3.93 ml/min/m2 for the two study groups, respectively. Furthermore, the differences in BMI from baseline were 1.91 and 2.14 kg/m2, respectively, for the two groups. The renal function was found to be improved after six months of treatment with modified antitubercular drugs. The intergroup comparisons were not statistically significant. CONCLUSION: We conclude that the modified regimen helps effectively cure pulmonary tuberculosis and significantly improves renal function in CKD patients. Further studies are required to generalize these findings.

Molecular and cellular remodeling of HepG2 cells upon treatment with antitubercular drugs.

Drug-induced liver injury (DILI) is an adverse outcome of the currently used tuberculosis treatment regimen, which results in patient noncompliance, poor treatment outcomes, and the emergence of drug-resistant tuberculosis. DILI is primarily caused by the toxicity of the drugs and their metabolites, which affect liver cells, biliary epithelial cells, and liver vasculature. However, the precise mechanism behind the cellular damage attributable to first-line antitubercular drugs (ATDs), as well as the effect of toxicity on the cell survival strategies, is yet to be elucidated. In the current study, HepG2 cells upon treatment with a high concentration of ATDs showed increased perforation within the cell, cuboidal shape, and membrane blebbing as compared with control/untreated cells. It was observed that ATD-induced toxicity in HepG2 cells leads to altered mitochondrial membrane permeability, which was depicted by the decreased fluorescence intensity of the MitoRed tracker dye at higher drug concentrations. In addition, high doses of ATDs caused cell damage through an increase in reactive oxygen species production in HepG2 cells and a simultaneous reduction in glutathione levels. Further, high dose of isoniazid (50-200 mM), pyrazinamide (50-200 mM), and rifampicin (20-100 µM) causes cell apoptosis and affects cell survival during toxic conditions by decreasing the expression of potent autophagy markers Atg5, Atg7, and LC3B. Thus, ATD-mediated toxicity contributes to the reduced ability of hepatocytes to tolerate cellular damage caused by altered mitochondrial membrane permeability, increased apoptosis, and decreased autophagy. These findings further emphasize the need to develop adjuvant therapies that can mitigate ATD-induced toxicity for the effective treatment of tuberculosis.

Esquema antituberculoso modificado por hepatotoxicidad causada por Pirazinamida: reporte de caso

Introducción: La tuberculosis es una de las 10 principales causas de muerte a nivel mundial. En 2020, causó 1,5 millones muertes. Se estima que llegó a 10,0 millones de nuevos casos durante el mismo año. Reporte de caso: varón de 93 años, antecedente de TBC pulmonar hace 15 años y contacto TBC actual. Presenta disnea y dolor pleurítico por 4 meses. Toracocentesis concluye exudado, biopsia pleural compatible con pleuritis granulomatosa no caseificante. Recibe esquema antituberculoso, desarrollando RAFA hepática. Se realiza reto farmacológico para diseñar un nuevo esquema de tratamiento. Paciente logra recuperarse. Se concluye que el manejo de tuberculosis debe individualizarse según paciente.

Introduction: Tuberculosis is one of the 10 leading causes of death worldwide. In 2020, it caused 1.5 million deaths. It is estimated that it reached 10.0 million new cases during the same year. Case of report: 93-year-old male, history of pulmonary TB 15 years ago and current TB contact. He presented dyspnea and pleuritic pain for 4 months. Thoracocentesis concludes exudate, pleural biopsy compatible with non-caseating granulomatous pleurisy. Receive antituberculosis regimen, developing hepatic RAFA. Pharmacological challenge is performed to design a new treatment scheme. Patient manages to recover. It is concluded that the management of tuberculosis should be individualized.

Evidence for Implementation: Management of TB in HIV and Pregnancy.

PURPOSE OF REVIEW: Pregnant people living with HIV (PLWH) are at especially high risk for progression from latent tuberculosis infection (LTBI) to active tuberculosis (TB) disease. Among pregnant PLWH, concurrent TB increases the risk of complications such as preeclampsia, intrauterine fetal-growth restriction, low birth weight, preterm-delivery, perinatal transmission of HIV, and admission to the neonatal intensive care unit. The grave impact of superimposed TB disease on maternal morbidity and mortality among PLWH necessitates clear guidelines for concomitant therapy and an understanding of the pharmacokinetics (PK) and potential drug-drug interactions (DDIs) between antitubercular (anti-TB) agents and antiretroviral therapy (ART) in pregnancy. RECENT FINDINGS: This review discusses the currently available evidence on the use of anti-TB agents in pregnant PLWH on ART. Pharmacokinetic and safety studies of anti-TB agents during pregnancy and postpartum are limited, and available data on second-line and newer anti-TB agents used in pregnancy suggest that several research gaps exist. DDIs between ART and anti-TB agents can decrease plasma concentration of ART, with the potential for perinatal transmission of HIV. Current recommendations for the treatment of LTBI, drug-susceptible TB, and multidrug-resistant TB (MDR-TB) are derived from observational studies and case reports in pregnant PLWH. While the use of isoniazid, rifamycins, and ethambutol in pregnancy and their DDIs with various ARTs are well-characterized, there is limited data on the use of pyrazinamide and several new and second-line antitubercular drugs in pregnant PLWH. Further research into treatment outcomes, PK, and safety data for anti-TB agent use during pregnancy and postpartum is urgently needed.

Assessing the protective effect of Crassocephalum vitellinum against Rifampicin-induced hepatotoxicity in Wistar rats.

Background: Crassocephalum vitellinum is widely used by traditional medical practitioners and local people in East Africa to manage a large number of ailments including hepatitis 1. However, its hepatoprotective effects had not been evaluated prior to this study. The aim of this study was to assess the effect of an ethanolic leaf extract of Crassocephalum vitellinum against rifampicin-induced liver toxicity in Wistar rats. Methods: Increasing doses of an ethanolic leaf extract of C. vitellinum were administered to Wistar rats daily for 35 days, together with rifampicin given orally as suspension. After the treatment period, Assessment of hepatoprotective activity was done by analysis of serum levels of biochemical and histopathological effects on the liver. Results: The results showed that administration of C. vitellinum extract significantly prevented drug- induced increase in serum levels of liver biomarker enzymes and also decreased the hepatocellular necrosis and inflammatory cells infiltration. Conclusion: The plant extract loweres the liver biomarker enzymes (ALT, ALP, AST) and preserves the histomorphology of the hepatocytes which is suggestive that the plant possess hepatoprotective properties.

Pott's disease (tuberculous spondylitis).

Pott's disease is a vertebral infection caused by Mycobacterium tuberculosis. Indolent nature and subacute course are associated with late diagnosis. A clinical case is presented whose diagnosis was delayed by atypical presentation with progressive worsening of symptoms. Magnetic resonance imaging (MRI) of the dorsolumbar spine revealed T7-T8 angulation suggestive of secondary injury, with intracanalar extension and spinal cord compression. Gastric aspirate cultures, direct microscopy, and polymerase chain reaction (PCR) were A 79-yearold female came to the emergency department with right back pain, pleuritic, with 12 h of evolution. Anorexia and weight loss,1 month evolution. Computed tomography (CT) of the dorsal spine revealed T7-T8 lytic lesions, suggestive of secondary nature. Objectively:weight loss and pain during thoracic palpation. Annalistically: normocytic/normochromic anemia, hypercalcemia, hepatic cholestasis, C-reactive protein (CRP) 7.12 mg/dL. Chest X-ray and electrocardiogram without alterations. She was admitted in Internal Medicine service. Analytically: hypophosphatemia, parathyroid hormone elevated, CRP 6 mg/dL, Beta-2 microglobulin elevated, dyslipidemia, iron and folicacid deficiency.negative for M. tuberculosis. T8 aspiration CT guided: cultures/direct microscopy negative, PCR positive for M. tuberculosis. Introductionof antitubercular drugs. Worsening of symptomatology, with paraparesia. MRI of the dorsal spine revealed spondylodiscitis and spinal cordcompression in T7-T8. Diagnosis revealed vertebral tuberculosis with spinal cord compression. She was transferred to neurosurgery servicefor surgical treatment. There was clinical and analytical improvement. Draws attention to difficulty in diagnose a treatable disease in a patientwith a rare presentation.

Pharmacovigilance of Antitubercular Therapy in Tuberculosis.

Background Adverse drug reactions (ADRs) to tuberculosis (TB) drugs are a significant concern for medical professionals and health authorities. Adverse events due to drug-resistant TB (DRTB) treatment are among the most important reasons for treatment interruption. Methods This study was an observational study conducted among patients diagnosed with TB (pulmonary/extrapulmonary) receiving antitubercular therapy (ATT) (first line/second-line drugs) irrespective of their age and gender. The patients who consented to participate, registered under National Tuberculosis Elimination Program (NTEP), Puducherry, during the study period from March 2020 to December 2020, were included in the study. The demographic details were recorded from the treatment card, and the participants were provided a diary to note down the adverse events. They were asked to report over the phone or during their visits to treatment centers for the first two months. During the follow-up (irrespective of their treatment phase [intensive/continuation]), the patients were assessed for symptoms and signs of common adverse events. Any adverse events reported by the patient were also recorded and analyzed for causality and severity. Results During the study period, 219 patients were included, of which 92 patients (42%) presented with adverse events. Among the patients with ADRs, 56.5% were males and 43.5% were females. The females were found to be at more risk than males for adverse events with the OR 1.871 (95% CI: 1.066-3.284). GI system was the most common body system involved (39%), followed by musculoskeletal system and skin disorders (24% and 21%), respectively. Most of the adverse events were latent in nature (60.9%), followed by sub-acute onset (28.3%) and acute events (6.5%). Maximum adverse events reported were mild to moderate (71.8%), followed by severe (18.5%). Most of the events were probable in nature (41.3%), and the definite category was 25% as per Naranjo's probability scale. Conclusion The current study shows the frequency of adverse events in patients receiving antitubercular drug therapy. The females were found to be at more risk than males for adverse events. It was found that the GI system was most affected as a known reaction to TB therapy followed by the musculoskeletal system. With more effective pharmacovigilance measures implementation, the adverse events being one of the factors for treatment interruption can be overcome.

The Medicinal Chemistry of Chalcones as Anti-Mycobacterium tuberculosis Agents.

Tuberculosis (TB), a highly fatal infectious disease, is caused by Mycobacterium tuberculosis (Mtb) that has inflicted mankind for several centuries. In 2019, the staggering number of new cases reached 10 million resulting in 1.2 million deaths. The emergence of multidrug-resistance- Mycobacterium tuberculosis (MDR-TB) and extensively drug-resistant-Mycobacterium tuberculosis (XDR-TB) is a global concern that requires the search for novel, effective, and safer short-term therapies. Nowadays, among the few alternatives available to treat resistant-Mtb strains, the majority have limitations, which include drug-drug interactions, long-term treatment, and chronic induced toxicities. Therefore, it is mandatory to develop new anti-Mtb agents to achieve health policy goals to mitigate the disease by 2035. Among the several bioactive anti-Mtb compounds, chalcones have been described as the privileged scaffold useful for drug design. Overall, this review explores and analyzes 37 chalcones that exhibited anti-Mtb activity described in the literature up to April 2021 with minimum inhibitory concentration (MIC90) values inferior to 20 µM and selective index superior to 10. In addition, the correlation of some properties for most active compounds was evaluated, and the main targets for these compounds were discussed.

Is 6 Months of Antitubercular Chemotherapy as Effective as More Than 6 Months Regimen in Spinal Tuberculosis? A Systematic Review and Meta-analysis.

Historically, osteoarticular tuberculosis (TB), including spinal TB, was treated with prolonged course of antitubercular therapy (ATT). Due to various challenges, there has been reluctance to explore the use of short-course ATT in spinal TB. However, with the success of short-course ATT being demonstrated in other forms of extrapulmonary TB, the subject is open for debate again. Therefore, we systematically reviewed various published literature to determine whether short-course treatment regimen (6 months) of ATT provides equivalent results in terms of disease healing as long-course treatment regimen (≥9 months) in the management of spinal TB. Five electronic databases (PubMed, MEDLINE, EMBASE, CENTRAL, and Web of Science) and their reference lists were searched to identify relevant randomized controlled trials with at least 1 year of follow-up that compared short-course with standard-course ATT for treatment of spinal TB. The methodological quality of included studies was assessed, and their data were extracted. A meta-analysis was used to calculate pooled effect sizes and 95% confidence interval (CI). The outcome measure was healed status of the disease at the final follow-up. Of 331 publications identified through literature search, eight publications describing six randomized studies were included. Moreover, 375 of 414 patients (90.58%) who received 6 months of ATT had healed status at their final follow-up compared to 404 of 463 patients (87.26%) who received ≥9 months of ATT. Overall, the healed status of spinal TB was equivalent in patients in both groups (pooled relative risk, 0.98; 95% CI, 0.92-1.04; p =0.439). However, there was considerable heterogeneity among the trials (I2=40.8%, p =0.149). The results suggest that the use of short-course (6 months) chemotherapy may be considered for the treatment of spinal TB in view of the similarity in the healing response achieved compared to treatment regimens of longer duration.

Two New Dihydrosphingosine Analogs Against Mycobacterium tuberculosis Affect gltA1, lprQ, and rpsO Expression.

The emergence of multidrug-resistant (MDR) Mycobacterium tuberculosis strains threaten the control of tuberculosis. New antitubercular dihydrosphingosine analogs, named UCIs, have been evaluated in preclinical studies but their cellular and molecular mechanisms of action against M. tuberculosis are still unknown. The aim of this study was to evaluate the effect of UCI exposure on gene expression of drug-sensitive H37Rv and MDR CIBIN:UMF:15:99 clones of M. tuberculosis which were isolated, phenotypically, and genetically characterized, cultured to log phase and treated with UCI compounds; followed by total RNA isolation, reverse transcription and hybridization assays on Affymetrix genomic microarrays. Data were validated with RT-qPCR assays. As results, UCI-05 and UCI-14 exposure increased gltA1 expression in drug-sensitive H37Rv clones. Furthermore, UCI-05 increased lprQ expression in MDR CIBIN:UMF:15:99 M. tuberculosis clones while UCI-14 reduced the expression of this gene in drug-sensitive H37Rv clones. In addition, UCI-05 reduced rpsO expression in drug-sensitive H37Rv clones. We found gene expression alterations that suggest these molecules may alter carbon and lipid metabolism as well as interfere in the protein-producing machinery in M. tuberculosis.

Prediction of potential drug interactions between repurposed COVID-19 and antitubercular drugs: an integrational approach of drug information software and computational techniques data.

INTRODUCTION: Tuberculosis is a major respiratory disease globally with a higher prevalence in Asian and African countries than rest of the world. With a larger population of tuberculosis patients anticipated to be co-infected with COVID-19 infection, an ongoing pandemic, identifying, preventing and managing drug-drug interactions is inevitable for maximizing patient benefits for the current repurposed COVID-19 and antitubercular drugs. METHODS: We assessed the potential drug-drug interactions between repurposed COVID-19 drugs and antitubercular drugs using the drug interaction checker of IBM Micromedex®. Extensive computational studies were performed at a molecular level to validate and understand the drug-drug interactions found from the Micromedex drug interaction checker database at a molecular level. The integrated knowledge derived from Micromedex and computational data was collated and curated for predicting potential drug-drug interactions between repurposed COVID-19 and antitubercular drugs. RESULTS: A total of 91 potential drug-drug interactions along with their severity and level of documentation were identified from Micromedex between repurposed COVID-19 drugs and antitubercular drugs. We identified 47 pharmacodynamic, 42 pharmacokinetic and 2 unknown DDIs. The majority of our molecular modelling results were in line with drug-drug interaction data obtained from the drug information software. QT prolongation was identified as the most common type of pharmacodynamic drug-drug interaction, whereas drug-drug interactions associated with cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) inhibition and induction were identified as the frequent pharmacokinetic drug-drug interactions. The results suggest antitubercular drugs, particularly rifampin and second-line agents, warrant high alert and monitoring while prescribing with the repurposed COVID-19 drugs. CONCLUSION: Predicting these potential drug-drug interactions, particularly related to CYP3A4, P-gp and the human Ether-à-go-go-Related Gene proteins, could be used in clinical settings for screening and management of drug-drug interactions for delivering safer chemotherapeutic tuberculosis and COVID-19 care. The current study provides an initial propulsion for further well-designed pharmacokinetic-pharmacodynamic-based drug-drug interaction studies. PLAIN LANGUAGE SUMMARY: Introduction:: Tuberculosis is a major respiratory disease globally with a higher prevalence in Asian and African countries than rest of the world. With a larger population of tuberculosis patients predicted to be infected with COVID-19 during this period, there is a higher risk for the occurrence of medication interactions between the medicines used for COVID-19 and tuberculosis. Hence, identifying and managing these interactions is vital to ensure the safety of patients undergoing COVID-19 and tuberculosis treatment simultaneously.Methods:: We studied the major medication interactions that could likely happen between the various medicines that are currently given for COVID-19 and tuberculosis treatment using the medication interaction checker of a drug information software (Micromedex®). In addition, thorough molecular modelling was done to confirm and understand the interactions found from the medication interaction checker database using specific docking software. Molecular docking is a method that predicts the preferred orientation of one medicine molecule to a second molecule, when bound to each other to form a stable complex. Knowledge of the preferred orientation may be used to determine the strength of association or binding affinity between two medicines using scoring functions to determine the extent of the interactions between medicines. The combined knowledge from Micromedex and molecular modelling data was used to properly predict the potential medicine interactions between currently used COVID-19 and antitubercular medicines.Results:: We found a total of 91 medication interactions from Micromedex. Majority of our molecular modelling findings matched with the interaction information obtained from the drug information software. QT prolongation, an abnormal heartbeat, was identified as one of the most common interactions. Our findings suggest that antitubercular medicines, mainly rifampin and second-line agents, suggest high alert and scrutiny while prescribing with the repurposed COVID-19 medicines.Conclusion:: Our current study highlights the need for further well-designed studies confirming the current information for recommending safe prescribing in patients with both infections.