Recent Biochemical Advances in Antitubercular Drugs: Challenges and Future.

Tuberculosis (TB) is one of the leading causes of death world-wide after AIDS. It infects around one-third of global population and approximately two million people die annually from this disease because it is a very contagious disease spread by Mycobacterium tuberculosis. The increasing number of drug-resistant strains and the failure of conventional treatments against this strain are the challenges of the coming decades. New therapeutic techniques aim to confirm cure without deterioration, to reduce deaths, contagions and the formation of drug-resistant strains. A plethora of new diagnostic tests are available to diagnose the active tuberculosis, screen latent M. tuberculosis infection, and to identify drug-resistant strains of M. tuberculosis. When effective prevention strategies do not prevail, high rates of early case detection and successive cures to control TB emergence would not be possible. In this review, we discussed the structural features of M. tuberculosis, Multi drug resistance tuberculosis (MDR-TB), extremely drug-resistant tuberculosis (XDR-TB), the mechanism of M. tuberculosis infection, the mode of action of first and second-line antitubercular drugs, the mechanism of resistance to the existing drugs, compounds in preclinical and clinical trial and drugs presently available for the treatment of tuberculosis. Moreover, the new diagnostic techniques to detect M. Tuberculosis are also discussed in this review.

Polymorphism of CYP3A4*18 is associated with anti-tuberculosis drug-induced hepatotoxicity.

Aim: The association between cytochrome P450 (CYP) gene polymorphisms and anti-tuberculosis drug-induced hepatotoxicity (ATDH) was investigated in patients with or without pre-existing liver diseases (PLD). Materials & methods: We followed 164 tuberculosis subjects, 58 with PLD and 106 without PLD. Polymorphisms in CYP2D6, CYP2C9, CYP2C19, CYP3A4 and CYP3A5 were analyzed using the TaqMan® SNP genotyping assay. Results: The CYP3A4*18 heterozygous genotype was associated with ATDH (OR: 3.24, 95% CI: 1.06-9.86) regardless of PLD presence. Among subjects without PLD, CYP3A4*18 heterozygotes had significantly higher ATDH risk (OR: 9.10, 95% CI: 1.56-53.16). Conversely, in the PLD group, CYP3A4*18 heterozygotes had lower ATDH risk (OR: 0.21, 95% CI: 0.05-0.98). Conclusion: CYP3A4*18 genotype is linked to ATDH in tuberculosis patients, with differential effects based on PLD presence.

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Managing Hepatotoxicity Caused by Anti-tuberculosis Drugs: A Comparative Study of Approaches.

BACKGROUND: Tuberculosis (TB) is one of the oldest and most well-known diseases that has been associated with humans for many years and remains a global health challenge today. Timely diagnosis and proper treatment are crucial for controlling and preventing the spread of the disease. While anti-TB drugs offer many benefits, inadequate monitoring can lead to a range of side effects, including hepatotoxicity, which is a major concern and can cause treatment discontinuation. The aim of this study was to determine the approach to the hepatotoxicity of anti-TB drugs and to investigate potential relationships between demographic factors, underlying medical conditions, and successful retreatment outcomes for hepatotoxicity induced by anti-TB drugs. METHODS: For this study, we reviewed the medical records of patients who experienced hepatotoxicity due to anti-TB treatment and were admitted to the infectious ward of Imam Khomeini Hospital between April 2015 and February 2019. The data were collected using a questionnaire. RESULTS: The findings indicated that the female gender, weight loss at the beginning of hospitalization, hepatitis C virus, hepatitis B virus (HBV), heart disease, and high levels of aspartate aminotransferase (AST) and alanine transaminase (ALT) at the beginning of hepatotoxicity are risk factors for failure to the retreatment of hepatotoxicity. There were two different approaches to the anti-TB retreatment regimen. The first approach involved gradually starting the drugs in full dose, while the second approach encompassed starting the drugs in the minimum dose and then increasing to the maximum dose. The results demonstrated no significant difference between the two approaches to managing hepatotoxicity induced by anti-TB drugs. CONCLUSION: Drug-induced hepatotoxicity is a common occurrence that often results in treatment discontinuation. Understanding the prevalence of this complication and identifying appropriate methods of rechallenge treatment is crucial to reducing complications and mortality rates.

Novel strategies based on natural products and synthetic derivatives to overcome resistance in Mycobacterium tuberculosis.

One of the biggest health challenges of today's world is the emergence of antimicrobial resistance (AMR), which renders conventional therapeutics insufficient and urgently demands the generation of novel antimicrobial strategies. Mycobacterium tuberculosis (M. tuberculosis), the pathogen causing tuberculosis (TB), is among the most successful bacteria producing drug-resistant infections. The versatility of M. tuberculosis allows it to evade traditional anti-TB agents through various acquired and intrinsic mechanisms, rendering TB among the leading causes of infectious disease-related mortality. In this context, researchers worldwide focused on establishing novel approaches to address drug resistance in M. tuberculosis, developing diverse alternative treatments with varying effectiveness and in different testing phases. Overviewing the current progress, this paper aims to briefly present the mechanisms involved in M. tuberculosis drug-resistance, further reviewing in more detail the under-development antibiotics, nanotechnological approaches, and natural therapeutic solutions that promise to overcome current treatment limitations.

QSPR analysis of distance-based structural indices for drug compounds in tuberculosis treatment.

Tuberculosis (TB) is one of the most contagious diseases that has a greater mortality rate than HIV/AIDS and the cases of TB are feared to rise as a repercussion of the COVID-19 pandemic. The pharmaceutical industry is constantly looking for ways to improve drug design processes in order to combat the growth of infections and cure newly identified syndromes or genetically based dysfunctions with the help of QSPR models. QSPR models are mathematical tools that establish relationships between a molecular structure and its physicochemical attributes using structural properties. Topological indices are such properties that are generated from the molecular graph without any empirically derived measurements. This work focuses on developing a QSPR model using distance-based topological indices for anti-tuberculosis medications and their diverse physicochemical features.

How do Mutations of Mycobacterium Genes Cause Drug Resistance in Tuberculosis?

A steady increase in the prevalence of drug-resistant tuberculosis (DR-TB) has already been reported in Pakistan. In addition, DR-TB is gradually changing from one-drug resistance to multi-drug resistance, which is a serious challenge for tuberculosis treatment. This review provides an overview of the anti-tuberculosis drugs and focuses on the molecular mechanisms of drug resistance in Mycobacterium tuberculosis, with the hope that it will contribute to the study of drug resistance in response to the emergence of multidrug-resistant tuberculosis.

Near-infrared molecular sensor for visualizing and tracking ONOO- during the process of anti-tuberculosis drug-induced liver damage.

Isoniazid (INH) and pyrazinamide (PZA) are both the first-line anti-tuberculosis drugs in clinical treatment. It is notable that there are serious side effects of the drugs along with upregulation of reactive nitrogen species, mainly including peripheral neuritis, gastrointestinal reactions, and acute drug-induced liver injury (DILI). Among them, DILI is the most common clinical symptom as well as the basic reason of treatment interruption, protocol change, and drug resistance. As vital reactive nitrogen species (RNS), peroxynitrite (ONOO-) has been demonstrated as a biomarker for evaluation and pre-diagnosis of drug-induced liver injury (DILI). In this work, we developed a red-emitting D-π-A type fluorescence probe DIC-NP which was based on 4'-hydroxy-4-biphenylcarbonitrile modified with dicyanoisophorone as a fluorescent reporter and diphenyl phosphinic chloride group as the reaction site for highly selective and sensitive sensing ONOO-. Probe DIC-NP displayed a low detection limit (14.9 nM) and 60-fold fluorescent enhancement at 669 nm in the sensing of ONOO-. Probe DIC-NP was successfully applied to monitor exogenous and endogenous ONOO- in living HeLa cells and zebrafish. Furthermore, we verified the toxicity of isoniazid (INH) and pyrazinamide (PZA) by taking the oxidative stress induced by APAP as a reference, and successfully imaged anti-tuberculosis drug-induced endogenous ONOO- in HepG2 cells. More importantly, we developed a series of mice models of liver injury and investigated the hepatotoxicity caused by the treatment of anti-tuberculosis drugs. At the same time, H&E of mice organs (heart, liver, spleen, lung, kidney) further confirmed the competence of probe DIC-NP for estimating the degree of drug-induced liver injury, which laid a solid foundation for medical research.

Host microbiome in tuberculosis: disease, treatment, and immunity perspectives.

Tuberculosis (TB), an airborne pulmonary disease caused by Mycobacterium tuberculosis (M. tb), poses an unprecedented health and economic burden to most of the developing countries. Treatment of TB requires prolonged use of a cocktail of antibiotics, which often manifest several side effects, including stomach upset, nausea, and loss of appetite spurring on treatment non-compliance and the emergence of antibiotic resistant M. tb. The anti-TB treatment regimen causes imbalances in the composition of autochthonous microbiota associated with the human body, which also contributes to major side effects. The microbiota residing in the gastrointestinal tract play an important role in various physiological processes, including resistance against colonization by pathogens, boosting host immunity, and providing key metabolic functions. In TB patients, due to prolonged exposure to anti-tuberculosis drugs, the gut microbiota significantly loses its diversity and several keystone bacterial taxa. This loss may result in a significant reduction in the functional potency of the microbiota, which is a probable reason for poor treatment outcomes. In this review, we discuss the structural and functional changes of the gut microbiota during TB and its treatment. A major focus of the review is oriented to the gut microbial association with micronutrient profiles and immune cell dynamics during TB infection. Furthermore, we summarize the acquisition of anti-microbial resistance in M. tb along with the microbiome-based therapeutics to cure the infections. Understanding the relationship between these components and host susceptibility to TB disease is important to finding potential targets that may be used in TB prevention, progression, and cure.

Impact of anti-tuberculosis treatment on hematological parameters in newly diagnosed tuberculosis patients at Jimma town: a longitudinal prospective study.

Tuberculosis (TB) is a significant public health problem affecting one-third of the world's population. In 2021, 1.6 million people died from TB. TB is the 13th leading cause of death and the second leading cause of infectious death after coronavirus disease 2019. Most anti-TB drugs affect hematological parameters in patients. Methods: This longitudinal prospective study was conducted from 03 January to 30 December 2019. Patients who completed a course of TB treatment were candidates for analysis. Sputum and blood samples were collected from each study participant and analyzed by the Gene X-pert machine and a HumaCount 30 hematology analyzer (Human GmbH). SPSS version 20 and R programming software version 4.2.3 were used for data analysis. Friedman's test was used to assess statistical significance. P-values ​​less than 0.05 were considered statistically significant. Results: A total of 148 patients who completed the course of TB treatment correctly were a candidate for final analysis. Ninety-one (61.5%) study participants were male; the median age was 27.6±9.8 years. Moreover, most of the study participants (84.4%) had pulmonary TB. Most of the hematological parameters had changed in the phases of TB treatment. After anti-TB treatment, there is a significant difference in hematological parameters in red blood cell count, hemoglobin concentration, hematocrit percentage, platelet count, and white blood cell count. Conclusion: Anemia and leucopenia are the most significant problems after TB treatment. Regular checking of these parameters is essential for the patient.

Standardization and validation of a novel UPLC-MS/MS method to quantify first line anti-tuberculosis drugs in plasma and dried blood spots.

Tuberculosis (TB) is a high-burden infectious disease with high prevalence and mortality rates. The first-line anti-TB drugs include isoniazid (INH), rifampicin (RMP), pyrazinamide (PZA), and ethambutol (EMB). At present, the standard method of blood sampling for therapeutic drug monitoring (TDM) analysis is venipuncture. Dried blood spots (DBS) are a minimally invasive method for collecting small quantities of whole blood from fingertips. The aim of the current study was to develop an ultrahigh-performance liquid chromatography technique coupled to tandem mass spectrometry (UPLC-MS/MS) for simultaneous quantification of the first-line anti-TB drugs in human plasma and DBS as a sampling alternative. The separation and detection conditions were optimized to quantify INH, RMP, PZA, and EMB in both matrices in an ACQUITY UPLC H Class system coupled to a XEVO TQD detector. Chromatographic separation was performed through an Acquity HSS T3 column (2.1 × 100 mm, 1.8 µm) with 0.1% formic acid in water and acetonitrile as the mobile phase. The total run time was 7 min for both methods, with retention time in plasma of 0.85, 1.22, 3.16, and 4.04 min and 0.74, 0.87, 0.97, and 4.16 min for EMB, INH, PZA, and RMP in DBS, respectively. The bioanalytical methods developed were proved selective, linear, precise, and accurate (inter- and intra-assay); the matrix effect was demonstrated to be within the established limits. Short- and long-term stability, freeze-thaw cycles for plasma, and short-term stability for DBS were established. A total of 15 patients with 46 ± 17 (mean ± SD) years old were included, and anti-TB drug concentrations were quantified on plasma and DBS as proof of concept. Based on RMP and INH plasma concentrations (Cp), and Bayesian estimation of individual pharmacokinetic parameters, a dose adjustment was necessary for 93% of patients. The slopes of the correlation lines between plasma and DBS concentrations of RMP, EMB, INH, and PZA were 0.5321, 0.8125, 0.5680, and 0.6791, respectively. Finally, significant correlations (p < 0.05) were observed between DBS and plasma concentrations for RMP (r2 = 0.6961), EMB (r2 = 0.4369), INH (r2 = 0.8675) and PZA (r2 = 0.7363). A simple, fast, and reliable UPLC-MS/MS method was developed to quantify first-line anti-TB drugs in plasma and DBS, which provides an easy sampling and storage to be applied as a new strategy for TDM in patients with TB.

Epidemiology-based wastewater monitoring for ecological risks of anti-tuberculosis drugs mixture effects.

First-line anti-tuberculosis (TB) drugs are commonly used to treat TB worldwide, leading to more contaminated wastewater being widely discharged into aquatic environments. However, studies of mixture interactions of anti-TB drugs and their residues in aquatic environments are scarce. This study aimed to determine the toxic interactions of anti-TB drugs-isoniazid (INH), rifampicin (RMP), and ethambutol (EMB)-in binary and ternary mixtures on Daphnia magna and used the epidemiology of TB history to construct epidemiology-based wastewater monitoring for assessing the environmental release of residues and related ecological risks. The acute immobilization of median effect concentrations (EC50) was 25.6 mg L-1 for INH, 80.9 mg L-1 for RMP, and 188.8 mg L-1 for EMB, as toxic units (TUs) for assessing mixture toxicity. The ternary mixture exhibited the lowest TUs at 50 % effects with 1.12, followed by 1.28 for RMP + EMB, 1.54 for INH + RMP, and 1.93 for INH + EMB, indicating antagonistic interactions. Nevertheless, the combination index (CBI) was used to examine the mixture toxicity in response to immobilization, revealing that the ternary mixture of CBI ranged from 1.01 to 1.08, tending to have a nearly additive effect when suffering >50 % effect (at high concentration levels). The forecasted environmentally relevant concentrations of anti-TB drugs have been on downward trends with ng L-1 level from 2020 to 2030 in Kaohsiung, Taiwan. Although ecotoxicological risks from the wastewater treatment plant and receiving water in the field were slightly greater than the prediction from epidemiology-based wastewater monitoring, there were no risk concerns. Here, we achieved the establishment of evidence that anti-TB drug mixtures' interaction and epidemiological-based monitoring support a systematic approach, resolving the absence of the mixture toxicity information for anti-TB mixture risk assessment in aquatic environments.

Regulation of Gut Microflora by Lactobacillus casei Zhang Attenuates Liver Injury in Mice Caused by Anti-Tuberculosis Drugs.

The gut-liver axis may provide a new perspective for treating anti-tuberculosis drug-induced liver injury (ATDILI). Herein, the protective effect of Lactobacillus casei (Lc) was investigated by modulating gut microflora (GM) and the toll like receptor 4 (TLR4)-nuclear factor (NF)-κB-myeloiddifferentiationfactor 88 (MyD88) pathway. C57BL/6J mice were given three levels of Lc intragastrically for 2 h before administering isoniazid and rifampicin for 8 weeks. Blood, liver, and colon tissues, as well as cecal contents, were collected for biochemical and histological examination, as well as Western blot, quantitative real time polymerase chain reaction (qRT-PCR), and 16S rRNA analyses. Lc intervention decreased alkaline phosphatase (ALP), superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), and tumor necrosis factor (TNF)-α levels (p < 0.05), recovered hepatic lobules, and reduced hepatocyte necrosis to alleviate liver injury induced by anti-tuberculosis drugs. Moreover, Lc also increased the abundance of Lactobacillus and Desulfovibrio and decreased Bilophila abundance, while enhancing zona occludens (ZO)-1 and claudin-1 protein expression compared with the model group (p < 0.05). Furthermore, Lc pretreatment reduced the lipopolysaccharide (LPS) level and downregulated NF-κB and MyD88 protein expression (p < 0.05), thus restraining pathway activation. Spearman correlation analysis indicated that Lactobacillus and Desulfovibrio were positively correlated with ZO-1 or occludin protein expression and negatively correlated with pathway protein expression. Desulfovibrio had significant negative relationships with alanine aminotransferase (ALT) and LPS levels. In contrast, Bilophila had negative associations with ZO-1, occludin, and claudin-1 protein expressions and positive correlations with LPS and pathway proteins. The results prove that Lactobacillus casei can enhance the intestinal barrier and change the composition of the gut microflora. Moreover, Lactobacillus casei may also inhibit TLR4-NF-κB-MyD88 pathway activation and alleviate ATDILI.

Drug Reaction With Eosinophilia and Systemic Symptoms-Associated Perimyocarditis After Initiation of Anti-tuberculosis Therapy: A Case Report.

A 34-year-old female who was recently placed on anti-tuberculosis medication with rifampin, isoniazid, pyrazinamide, and levofloxacin therapy for suspected tuberculosis reinfection presented with subjective fevers, rash, and generalized fatigue. Labs showed signs of end-organ damage with eosinophilia and leukocytosis. One day later, the patient became hypotensive with a worsening fever, and an electrocardiogram showed new diffuse ST segment elevations with an elevated troponin. An echocardiogram revealed a reduction in ejection fraction with diffuse hypokinesis, and cardiac magnetic resonance imaging (MRI) showed circumferential myocardial edema with subepicardial and pericardial inflammation. Prompt diagnosis of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome using the European Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria and discontinuation of therapy was initiated. Due to the hemodynamic instability of the patient, the patient was started on systemic corticosteroids and cyclosporine, with the improvement of her symptoms and rash. A skin biopsy was performed, which revealed perivascular lymphocytic dermatitis, consistent with DRESS syndrome. As the patient's ejection fraction improved spontaneously with corticosteroids, the patient was discharged with oral corticosteroids, and a repeat echocardiogram showed full recovery of ejection fraction. Perimyocarditis is a rare complication of DRESS syndrome that is associated with degranulation and the release of cytotoxic agents into myocardial cells. Early discontinuation of offending agents and initiation of corticosteroids are essential to rapid recovery of ejection fraction and improved clinical outcomes. Multimodality imaging, including MRI, should be used to confirm perimyocardial involvement and guide the necessity for mechanical support or transplant. Further research should be on the mortality of DRESS syndrome with and without myocardial involvement, with an increased emphasis on cardiac evaluation in DRESS syndrome.

Effects of second-line anti-tuberculosis drugs on the intestinal microbiota of patients with rifampicin-resistant tuberculosis.

Objective: To determine the effects of second-line anti-tuberculosis (TB) drugs on the composition and functions of intestinal microbiota in patients with rifampicin-resistant TB (RR-TB). Methods: In this cross-sectional study, stool samples and relevant clinical information were collected from patients with RR-TB admitted to the Drug-resistant Specialty Department at Hunan Chest Hospital (Hunan Institute For Tuberculosis Control). The composition and functions of intestinal microbiota were analyzed using metagenomic sequencing and bioinformatics methods. Results: Altered structural composition of the intestinal microbiota was found when patients from the control, intensive phase treatment, and continuation phase treatment groups were compared (P<0.05). Second-line anti-TB treatment resulted in a decrease in the relative abundance of species, such as Prevotella copri, compared with control treatment. However, the relative abundance of Escherichia coli, Salmonella enterica, and 11 other conditionally pathogenic species increased significantly in the intensive phase treatment group. Based on differential functional analysis, some metabolism-related functions, such as the biosynthesises of phenylalanine, tyrosine, and tryptophan, were significantly inhibited during second-line anti-TB drug treatment, while other functions, such as phenylalanine metabolism, were significantly promoted during the intensive phase of treatment. Conclusion: Second-line anti-TB drug treatment caused changes in the structural composition of the intestinal microbiota in patients with RR-TB. In particular, this treatment induced a significant increase in the relative abundance of 11 conditionally pathogenic species, including Escherichia coli. Functional analysis revealed significantly decreased biosynthesises of phenylalanine, tyrosine, and tryptophan and significantly increased phenylalanine metabolism.

Pharmacokinetics of rifampicin, isoniazid & pyrazinamide during daily & intermittent dosing: A preliminary study.

Background & objectives: The National Tuberculosis (TB) Control Programme has transitioned from thrice-weekly to daily drug treatment regimens in India. This preliminary study was conceived to compare the pharmacokinetics of rifampicin (RMP), isoniazid (INH) and pyrazinamide (PZA) in TB patients being treated with daily and thrice weekly anti-TB treatment (ATT). Methods: This prospective observational study was undertaken in 49 newly diagnosed adult TB patients receiving either daily ATT (n=22) or thrice-weekly ATT (n=27). Plasma RMP, INH and PZA were estimated by high-performance liquid chromatography. Results: The peak concentration (Cmax) of RMP was significantly higher (RMP: 8.5 µg/ml vs. 5.5 µg/ml; P=0.003) and Cmax of INH was significantly lower (INH: 4.8 µg/ml vs. 10.9 µg/ml; P<0.001) in case of daily dosing compared to thrice-weekly ATT. Cmax of drugs and doses was significantly correlated. A higher proportion of patients had subtherapeutic RMP Cmax (8.0 µg/ml) during thrice-weekly compared to daily ATT (78% vs. 36%; P=0.004). Multiple linear regression analysis showed that Cmax of RMP was significantly influenced by the dosing rhythm, pulmonary TB and Cmax of INH and PZA by the mg/kg doses. Interpretation & conclusions: RMP concentrations were higher and INH concentrations were lower during daily ATT, suggesting that INH doses may need to be increased in case of a daily regimen. Larger studies are, however, required using higher INH doses when monitoring for adverse drug reactions and treatment outcomes.

Insights into therapeutic liquid mixtures and formulations towards tuberculosis therapy.

Therapeutic liquid mixtures, as deep eutectic systems, are considered a sustainable strategy that can be useful for the modification and enhancement of the pharmacokinetics and pharmacodynamics of different active ingredients. In this study, we assessed the stability and antibacterial activity of therapeutic liquid formulations prepared with anti-tuberculosis drugs. Tuberculosis therapy presents various pitfalls related, for example, to the administration of prolonged regimens of multiple drugs, different severe adverse effects, low compliance of the patient to treatment and the development of drug resistance. During this study, it was possible to assess the physicochemical stability of the formulations for 6 months, by polarized optical microscopy, 1H NMR and FTIR-ATR. Furthermore, the mixtures present an antibacterial effect against a drug-susceptible Mycobacterium tuberculosis strain (H37Rv). This was particularly evident for the mixtures with ethambutol incorporated, making them interesting to pursue with further studies and evaluation of clinical applicability. Upon infection, it was also observed that a single and higher dose appears to be more effective than lower separate doses, which could allow the production of patient-friendly formulations.

Hepatocyte ferroptosis contributes to anti-tuberculosis drug-induced liver injury: Involvement of the HIF-1α/SLC7A11/GPx4 axis.

Anti-tuberculosis drug-induced liver injury (ATB-DILI) is a common serious adverse event observed during the clinical treatment of tuberculosis. However, the molecular mechanisms underlying ATB-DILI remain unclear. A recent study has indicated that ferroptosis and lipid peroxidation may be involved in liver injury. Therefore, this study aimed to investigate the role of ferroptosis in the molecular mechanisms underlying ATB-DILI. Our results showed that anti-TB drugs induced hepatocyte damage in vivo and in vitro and inhibited BRL-3A cell activity in a dose-dependent manner, accompanied by increased lipid peroxidation and reduced antioxidant levels. Moreover, ACSL4 expression and Fe2+ concentration significantly increased following anti-TB drug treatment. Interestingly, anti-TB drug-induced hepatocyte damage was reversed by ferrostatin-1 (Fer-1, a specific ferroptosis inhibitor). In contrast, treatment with erastin (a ferroptosis inducer) resulted in further elevation of ferroptosis indicators. Additionally, we also found that anti-TB drug treatment inhibited HIF-1α/SLC7A11/GPx4 signaling in vivo and in vitro. Notably, HIF-1α knockdown significantly enhanced anti-TB drug-induced ferroptotic events and the subsequent exacerbation of hepatocyte damage. In conclusion, our findings indicated that ferroptosis plays a crucial role in the development of ATB-DILI. Furthermore, anti-TB drug-induced hepatocyte ferroptosis was shown to be regulated by HIF-1α/SLC7A11/GPx4 signaling. These findings shed new light on the mechanisms underlying ATB-DILI and suggest novel therapeutic strategies for this disease.

Study of drug interaction, mutant frequency and mutant prevention concentration of DFMBT against Mycobacterium tuberculosis H37RV.

In the present study 7,7-Dimethyl-4-(4-trifluoromethyl-phenylamino)-2,4,4a,6,7,8-hexahydro-benzo[d] [1,3]thiazin-5-one (DFMBT) was synthesized and evaluated for in vitro activity against Mycobacterium tuberculosis (M.tb) H37RV. Results demonstrated that at 64x MIC, DFMBT completely sterilized the TB culture from day 4 of the incubation whereas at 32 and 16x MIC, it sterilized the TB culture from day 8. The bacterial cultures were completely sterilized by DFMBT at 8x MIC from day 16 of incubation. DFMBT showed 1.5 µg/mL MIC value as compared to the standard anti-tuberculosis drugs using broth macro-dilution method. The MBC value of DFMBT was found to be 6.0 µg/mL whereas for INH, RIF, AMK and LVX the values were found to be 0.312, 0.156, 5.0 and 5.0 µg/mL, respectively. The DFMBT in combination with INH/RIF or AMK showed the ∑FIC value of 0.258, 0.252 and 0.453, respectively indicating synergistic interaction. Moreover, the value of ∑FIC for the combination of DFMBT with LVX was found to be 1.33 suggesting and additive interaction. The post antibiotic effect of DFMBT at 1x and 64x MIC was found to be 29.89 ± 10.12 and 158.75 ± 17.50 h, respectively. The DFMBT showed an MPC value of 150 µg/mL which was intermediate between INH and RIF. In summary, DFMBT exhibits bacteriostatic as well as bactericidal effect on Mycobacterium tuberculosis H37RV. It has synergistic interaction with INH, RIF and AMK anti-TB drugs, descent post antibiotic effect, mutation frequency and mutant prevention concentration. Thus, DFMBT may be developed as an effective agent as anti-TB compound.

GenoType MTBDRsl for detection of second-line drugs and ethambutol resistance in multidrug-resistant Mycobacterium tuberculosis isolates at a high-throughput laboratory.

We assessed the performance of MTBDRsl for detection of resistance to fluoroquinolones, aminoglycosides/cyclic peptides, and ethambutol compared to BACTEC MGIT 960 by subjecting simultaneously to both tests 385 phenotypically multidrug-resistant-Mycobacterium tuberculosis isolates from Sao Paulo, Brazil. Discordances were resolved by Sanger sequencing. MTBDRsl correctly detected 99.7% of the multidrug-resistant isolates, 87.8% of the pre-XDR, and 73.9% of the XDR. The assay showed sensitivity of 86.4%, 100%, 85.2% and 76.4% for fluoroquinolones, amikacin/kanamycin, capreomycin and ethambutol, respectively. Specificity was 100% for fluoroquinolones and aminoglycosides/cyclic peptides, and 93.6% for ethambutol. Most fluoroquinolone-discordances were due to mutations in genome regions not targeted by the MTBDRsl v. 1.0: gyrA_H70R and gyrB_R446C, D461N, D449V, and N488D. Capreomycin-resistant isolates with wild-type rrs results on MTBDRsl presented tlyA mutations. MTBDRsl presented good performance for detecting resistance to second-line drugs and ethambutol in clinical isolates. In our setting, multidrug-resistant. isolates presented mutations not targeted by the molecular assay.

Clinical characteristics of liver injury caused by anti-tuberculosis drugs in newly treated pulmonary tuberculosis patients co-infected with hepatitis B virus / 公共卫生与预防医学

Objective To investigate the clinical characteristics of drug-induced liver injury caused by anti-tuberculosis drugs in newly treated pulmonary tuberculosis patients with hepatitis B virus (HBV). Methods A total of 133 patients with pulmonary tuberculosis and HBV who were treated in Zhuzhou Central Hospital from January 2018 to early January 2022 were selected, and all were treated with conventional anti-tuberculosis 2HRZE/4HR regimen. According to the liver injury, the patients were divided into liver injury group and no liver injury group. Univariate analysis was used to analyze the related factors of liver injury caused by anti-tuberculosis drugs, and multivariate logistic regression analysis was used to analyze the independent risk factors of liver injury caused by anti-tuberculosis drugs. Results Among 133 cases of newly treated pulmonary tuberculosis patients with HBV, 24 cases had liver injury caused by anti-tuberculosis drugs, accounting for 18.05%; 109 patients had no liver injury caused by anti-tuberculosis drugs, accounting for 81.95%. Univariate analysis showed that there were significant differences in smoking history, drinking history, diabetes history, hypertension history, anti-tuberculosis treatment plan, malnutrition, and use of hepatoprotective drugs between the liver injury group and the no liver injury group (P<0.05). Multivariate logistic regression analysis showed that smoking history, drinking history, diabetes history, hypertension history, PZA-containing regimen, malnutrition, and no use of hepatoprotective drugs were independent risk factors for liver injury caused by anti-tuberculosis drugs. Conclusion Smoking history, drinking history, diabetes history, hypertension history, PZA-containing regimen, malnutrition, and no use of hepatoprotective drugs are the risk factors for drug-induced liver injury caused by anti-tuberculosis drugs in newly treated pulmonary tuberculosis patients with HBV.