Anti-tuberculosis Research Articles

New polycyclic tetramate macrolactams with antimycobacterial activity produced by marine-derived Streptomyces sp. KKMA-0239.

During our screening for anti-mycobacterial agents against Mycobacterium avium complex (MAC), two new polycyclic tetramate macrolactams (PTMs), named hydroxycapsimycin (1) and brokamycin (2), were isolated along with the known PTM, ikarugamycin (3), from the culture broth of marine-derived Streptomyces sp. KKMA-0239. The relative structures of 1 and 2 were elucidated by spectroscopic data analyses, including 1D and 2D NMR. Furthermore, the absolute configuration of 1 was confirmed by a single-crystal X-ray diffraction analysis. Compounds 2 and 3 exhibited moderate antimycobacterial activities against MAC, including clinically isolated drug-resistant M. avium.

Miliary tuberculosis diagnosed by diffuse hepatic uptake on PET/CT and transjugular liver biopsy.

The patient was an 81-year-old man. In his 20s, he had been treated with pharmacotherapy for pulmonary tuberculosis for 1 year. He presented to the Department of Respiratory Medicine with a chief complaint of dyspnea. The possibility of respiratory disease appeared to be low, but hepatic impairment was detected. The patient was thus referred to our department. Though the cause of hepatic impairment was unknown, the soluble interleukin-2 receptor level was elevated, suggesting malignant lymphoma. 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)-computed tomography (CT) revealed diffuse, homogenous, intense FDG uptake in the entire liver, and transjugular liver biopsy confirmed the diagnosis. Histopathological examination revealed an epithelioid granuloma, and auramine staining was positive for bacilli suggestive of tuberculosis. CT revealed diffuse micronodular shadows in the lung, yielding a diagnosis of miliary tuberculosis. Therefore, the patient was prescribed antituberculosis medication by the Department of Respiratory Medicine. His subsequent clinical course was good. The miliary (hepatic) tuberculosis was typical based on the diffuse, homogenous, intense FDG uptake throughout the liver observed on PET-CT.

Perspectives on Determinants of Poor Adherence to Anti-Tuberculosis Drugs amongst Patients Attending a Tuberculosis Treatment Center in South East, Nigeria

Background of the study: Tuberculosis is curable and preventable as long as the infected patients take their medication as prescribed without interruption and all preventive measures observed both within the hospital and the community. Adherence to tuberculosis treatment by tuberculosis patients is key to the global control of tuberculosis. Methods: This cross sectional study was carried out at the Mile-4 hospital, a tuberculosis treatment center in Abakaliki, Ebonyi State, Nigeria. A total of 125 tuberculosis patients were recruited for the study and self-administered questionnaires and focus group discussions were used to get responses from the patients. Descriptive and inferential statistics with the aid of SPSS version 20 was used for data analysis. Results: Major reasons given for missing appointment and not following treatment schedule closely were lack of money, long distance from health facility, inadequate health education and non provision of food. Lack of money and long distance from health facility accounted for 60.9% of the reasons for not adhering to the treatment schedule by the tuberculosis patients. Conclusion: Adherence to tuberculosis treatment can be facilitated by extensive health education, minimal financial support and provision of food to tuberculosis patients. Distance from health facilities is also very important in the adherence to anti tuberculosis therapy by tuberculosis patients.

Improved in vitro potency of Clofazimine derivatives against Neisseria species

Globally, millions of infections that are resistant to antimicrobial agents are reported annually, leading to more than 700,000 fatalities. Among all, challenges arise particularly from nontuberculosis mycobacterial (NTM) and Gram-negative bacteria, as they exhibit limited treatment options in light of increasing reports of multi-drug resistant strains.Clofazimine (CFZ) is an antimycobacterial medication used to treat leprosy, and it is also known for its side effect of inducing skin pigmentation. The use of CFZ and its analogues against a broad range of Gram-negative bacteria has not been extensively investigated. In this study, we designed, synthesized and studied 11 CFZ analogues and identified examples with comparable or improved in vitro anti-bacterial activity relative to that of CFZ itself. This is the first report demonstrating in vitro activity of CFZ and its analogues against Neisseria species. The results of these studies may facilitate the development of CFZ analogues with limited side effects in humans.

Management of anti-tuberculosis drug induced xerostomia in completely edentulous patient-A case report

Tuberculosis (TB) is one of the major systemic conditions which is a preventable and curable infection but remains a significant cause of death and reduced quality of life of patients.Weight loss, tiredness and loss of appetite are common symptoms that are even more aggravated in geriatric patients affecting the quality of life of the patient.Edentulism, hyposalivation and dryness of the mouth further contribute to the discomfort in patients wearing dentures that leads to the weight reduction, indigestion and loss of appetite in such patients. Compromised esthetics and speech of the patient just multiply the social trauma and isolation the patient is already facing due to TB.This paper describes a novel method of managing a patient with active TB on Anti Tuberculosis therapy (ATT) reporting symptoms of xerostomia.Completely Edentulous Maxillary and Mandibular Residual Alveolar Ridges: PDI Class II with associated ATT-induced Xerostomia.Split denture with a salivary reservoir in the mandibular denture.Improved aesthetics & speech, improved mastication and reduced weight loss due to denture wearing.Split dentures with artificial saliva can increase the patient's comfort in wearing dentures which overturns the impact of infection significantly and leads to increased quality of life in edentulous patients on ATT.

Niosomal Drug Delivery System used in Tuberculosis

Niosomes are artificially manufactured vesicles made of Cholesterol and Non-ionic surfactant. Their capacity to encapsulate a broad variety of pharmaceuticals and shield them from deterioration has piqued interest in drug delivery. Niosomes have demonstrated a possible use in the administration of anti-tuberculosis medications. Worldwide, tuberculosis is a serious public health concern. Even with advances in science and technology, tuberculosis remains a persistent problem.Niosomes can encapsulate anti-TB drugs, protecting them from enzymatic degradation and allowing for sustained release. Research in this field is on-going, with scientists working on optimizing niosomal formulations for tuberculosis treatment. It's important to consult current scientific literature for the latest advancements. Some anti-tubercular drugs face challenges in terms of absorption and bioavailability. Niosomal delivery systems can help address these issues. While niosomal drug delivery systems show promise, it's crucial to note that they are still an area of active research and specific formulations and protocols may vary. Patients should always consult with their healthcare providers for the most appropriate and up-to-date treatment options for tuberculosis. Niosomes can encapsulate both hydrophilic and lipophilic drugs, offering advantages such as increased drug stability, prolonged circulation time, controlled release, and targeted delivery. They have applications in various fields including pharmaceuticals, cosmetics, and agriculture.
 Keywords: Tuberculosis, Niosomes, Drug delivery system

The Indiscriminate Chemical Makeup of Secondary Metabolites Derived from Endophytes Harvested from Aloe barbadensis Miller in South Africa's Limpopo Region.

The efficacy of 23 bacterial isolates obtained from surface-sterilized stems and leaves of three medicinal plants (Aloe barbadensis Miller, Artemisia afra, and Moringa oleifera) was investigated in an endeavour to prevent the growth of Mycobacterium bovis using the cross-streak method. Endophytes were isolated by incubating sterile plant materials on nutrient agar at 30 °C for 5 days. Two isolates showing activity were subsequently utilized to produce the extracts. Whole-genome sequencing (WGC) was used to identify the isolates. Secondary metabolites produced after 7 days of growth in nutrient broth were harvested through extraction with ethyl acetate. The extracts were chemically profiled using gas chromatography-high resolution time-of-flight mass spectrometry (GC-HRTOF-MS). NCBI BLAST search results revealed that the isolated endophytes belonged to the Pseudomonas and Enterobacter genera, based on WGC. Two endophytes, Aloe I4 and Aloe I3-I5 from Aloe barbadensis, exhibited potency based on the cross-streak method. The metabolite profiling of the selected endophytes identified 34 metabolites from Aloe I4, including ergotamine, octadecane, L-proline and 143 other metabolites including quinoline and valeramide, which inhibit microbial quorum sensing. These findings suggest that bacterial endophytes from medicinal plants, particularly Aloe barbadensis, hold promise as sources of antimycobacterial agents for human health applications.

Biofilm Formation in Mycobacterial Genus; Mechanism of Biofilm Formation and Anti-Mycobacterial Biofilm Agents.

Mycobacterium tuberculosis, Mycobacterium leprae, and non-tuberculous mycobacteria (NTM) are among the most significant human pathogens within the Mycobacterium genus. These pathogens can infect people who come into contact with biomaterials or have chronic illnesses. A characteristic pathogenic trait of mycobacteria is the development of biofilms, which involves several molecules, such as the GroEL1 chaperone, glycopeptidolipids, and shorter-chain mycolic acids. Bacterial behavior is influenced by nutrients, ions, and carbon sources, which also play a regulatory role in biofilm development. Compared to their planktonic phase, mycobacterial biofilms are more resilient to environmental stresses and disinfectants. Mycobacteria that produce biofilms have been found in several environmental studies, particularly in water systems. NTM can cause respiratory problems in individuals with underlying illnesses such as cystic fibrosis, bronchiectasis, and old tuberculosis scars. Mycobacteria that grow slowly, like those in the Mycobacterium avium complex (MAC), or rapidly, like Mycobacterium abscessus, can be pathogens. Infections related to biomaterials represent a significant category of biofilm-associated infections, with rapidly growing mycobacteria being the most frequently identified organisms. A biofilm produced by M. tuberculosis can contribute to caseous necrosis and cavity formation in lung tissue. Additionally, M. tuberculosis forms biofilms on clinical biomaterials. Biofilm formation is a major contributor to antimicrobial resistance, providing defense against drugs that would typically be effective against these bacteria in their planktonic state. The antibiotic resistance of biofilm-forming microbes may render therapy ineffective, necessitating the physical removal of biofilms to cure the infection. Recently, new approaches have been developed with potential anti-biofilm compounds to increase treatment effectiveness. Understanding biofilms is crucial for the appropriate treatment of various NTM diseases, and the recent discovery of M. tuberculosis biofilms has opened up a new field of study. This review focuses on the biofilm formation of the Mycobacterial genus, the mechanisms of biofilm formation, and anti-mycobacterial biofilm agents.

Pengaruh Telenursing Whatsapp Chatbot Terhadap Kepatuhan Minum Obat (OAT) Di Puskesmas Benteng Kota Sukabumi

Health problems that are of global concern are infectious diseases, one of which is tuberculosis (TB). Indonesia is one of the eight countries that contributes the most TB cases worldwide, and is ranked third after India and China (WHO, 2021). Non-compliance with taking medication is the main factor causing TB treatment failure, which reaches 50% (Aisyan, 2018). An innovation that can be done to overcome non-compliance with taking medication is the WhatsApp chatbot telenursing program. The aim of this research is to determine whether there is an effect of WhatsApp chatbot telenursing on medication adherence (OAT) in tuberculosis sufferers at Benteng Sukabumi City Health Center. This research method is experimental research with a pre-experimental one group pre-test post-test research design. The population in this study were all TB-SO and TB-RO patients who were undergoing treatment at Benteng Health Center with a total population of 51 patients. Sampling used a total sample technique according to inclusion and exclusion criteria so that the required sample was 45 respondents. The results of the study showed that there was an increase in medication compliance behavior from before the intervention, 9 respondents were compliant, after the intervention there were 44 respondents who were compliant in taking medication, and the Wilcoxon test results obtained a p-value of 0.000 < 0.05 so that H1 was accepted and existed. The influence of the WhatsApp chatbot telenursing program on compliance with anti-tuberculosis medication (OAT) in tuberculosis sufferers at Benteng Sukabumi City Health Center

Tuberculosis: Pharmacognosy, Medicinal Plant Raw Materials, Medicinal Plants, Phytotherapy

The article delves into the crucial role that medicinal plants could play in combating tuberculosis, highlighting their vast diversity and their proven efficacy in health preservation. As the quest for effective drugs advances, there's a growing emphasis on harnessing both unique chemical compounds and natural plant-based components. This innovative approach opens up new avenues in battling the infection caused by Mycobacterium tuberculosis. The piece underscores the significance of continued investigation into the medicinal use of plants as adjunctive therapies in tuberculosis treatment. One of the key challenges identified is the complex interaction between antituberculosis medications and herbal components, an area that remains largely unexplored. The intricacies of how these interactions occur and their impact on the effectiveness of treatment are still not well understood. The article points out that meticulous and detailed research is essential for unlocking the potential of active biomolecules found in plants, which could pave the way for the development of novel therapeutic agents. Furthermore, it stresses the importance of conducting comprehensive evaluations regarding the interactions and safety of these plant-derived substances under various experimental setups. Such research is not only pivotal for enhancing our understanding of the synergistic effects between pharmaceuticals and plant-based compounds but also for ensuring the safety and efficacy of new treatments. By focusing on these aspects, the scientific community can make significant strides in identifying and utilizing natural resources in the fight against tuberculosis, potentially leading to more effective and safer treatment options.

Clinical characteristics and outcome of genitourinary tuberculosis in Balochistan: An observational study.

Objective: To make aware that the healthcare professionals should diagnose GUTB as early as possible to avoid the grave side effects of untreated cases as it can lead to the gross structural abnormalities in the Genito urinary system. Study Design: Single Center Observational study. Setting: Tertiary Care Medicine Unit in Baluchistan, in BMCH Teaching Hospital. Period: 1st January 2012 to 31st Dec 2022. Material & Methods: Total 118 patients were enrolled in the research and patients were taken a detailed history, they went through physical examination, then they went they underwent through different diagnostic modalities as per the availability in indications. The diagnosed cases were treated and the follow up was done the mean duration for the follow up was around two years. Results: All individuals received interventions primarily involving anti-tuberculosis medications. Three patients had bilateral fallopian tubes obstruction who went under laparoscopy and later on 1 couple opted for IVF, for infertility. Anti-TB drug therapy resulted in severe adverse reactions in 8 individuals. Among them, two female patients experienced the formation of a thimble bladder accompanied by incapacitating storage symptoms. Additionally, at the time of diagnosis, 4 patients exhibited impaired renal functions, which, fortunately, remained unaltered following the completion of the prescribed treatment. None of our patients went into ESRD, and no death during study was reported due to GUTB. Conclusion: It was concluded in our study that Genito urinary tuberculosis being the second commonest type of extrapulmonary tuberculosis is also common in Baluchistan and it needs to be treated and diagnosed and treated as soon as possible, we also suggest that if the expert diagnostic modalities for the diagnosis of GUTB are not available even the clinical suspicion can be used to diagnose the case and start the treatment.

Diagnosis of multiple tuberculous muscle abscesses in a patient with systemic lupus erythematosus by metagenomic next-generation sequencing- a case report and literature review

BackgroundEarly diagnosis of muscular tuberculosis (TB) without coexistent active skeletal involvement is often challenging because the disease is very rare and its clinical manifestation is nonspecific and misleading. To raise the awareness and emphasize early diagnosis of muscular TB, we present a case of multiple tuberculous muscle abscesses in a systemic lupus erythematosus (SLE) female, but without pulmonary tuberculosis (PTB), in order to increase awareness of and stress the need of early detection of muscular TB.Case presentationA 44-year-old woman with a 6-year history of SLE who had been treated with methylprednisolone for a long time complained of erythema on her trunk and extremities for five months, along with edema and myalgia for two months, and fever for one month. The patient was first misdiagnosed as SLE overlap dermatomyositis. However, an ultrasound-guided drainage of muscle abscesses revealed positive acid-fast staining combined with positive deoxyribonucleic acid fragment of Mycobacterium tuberculosis using metagenomic next-generation sequencing (mNGS). The patient was cured and released following standard anti-tuberculosis medication, local puncture drainage, and an intravitreal injection of streptomycin. Literature search found only 19 cases of tuberculous muscle abscesses occurring in the extremities reported from 1999 to 2023.ConclusionsExtrapulmonary TB with predominantly muscle involvement is rare and with no specific clinical presentation. Muscular tuberculosis may be disdiagnosed for dermatomyositis due to the high muscle enzyme levels, delaying diagnosis and treatment. mNGS technology is helpful in the early and rapid diagnosis of muscular TB. On the basis of traditional anti-tuberculosis treatment, an ultrasound-guided percutaneous puncture drainage and intracavitary injection of streptomycin for the treatment of tuberculous muscle abscess is easy to operate, safe and effective, which is worthy of clinical popularization and application.

Synergistic toxicity with copper contributes to NAT2-associated isoniazid toxicity

Anti-tuberculosis (AT) medications, including isoniazid (INH), can cause drug-induced liver injury (DILI), but the underlying mechanism remains unclear. In this study, we aimed to identify genetic factors that may increase the susceptibility of individuals to AT-DILI and to examine genetic interactions that may lead to isoniazid (INH)-induced hepatotoxicity. We performed a targeted sequencing analysis of 380 pharmacogenes in a discovery cohort of 112 patients (35 AT-DILI patients and 77 controls) receiving AT treatment for active tuberculosis. Pharmacogenome-wide association analysis was also conducted using 1048 population controls (Korea1K). NAT2 and ATP7B genotypes were analyzed in a replication cohort of 165 patients (37 AT-DILI patients and 128 controls) to validate the effects of both risk genotypes. NAT2 ultraslow acetylators (UAs) were found to have a greater risk of AT-DILI than other genotypes (odds ratio [OR] 5.6 [95% confidence interval; 2.5–13.2], P = 7.2 × 10−6). The presence of ATP7B gene 832R/R homozygosity (rs1061472) was found to co-occur with NAT2 UA in AT-DILI patients (P = 0.017) and to amplify the risk in NAT2 UA (OR 32.5 [4.5–1423], P = 7.5 × 10−6). In vitro experiments using human liver-derived cell lines (HepG2 and SNU387 cells) revealed toxic synergism between INH and Cu, which were strongly augmented in cells with defective NAT2 and ATP7B activity, leading to increased mitochondrial reactive oxygen species generation, mitochondrial dysfunction, DNA damage, and apoptosis. These findings link the co-occurrence of ATP7B and NAT2 genotypes to the risk of INH-induced hepatotoxicity, providing novel mechanistic insight into individual AT-DILI susceptibility.Yoon et al. showed that individuals who carry NAT2 UAs and ATP7B 832R/R genotypes are at increased risk of developing isoniazid hepatotoxicity, primarily due to the increased synergistic toxicity between isoniazid and copper, which exacerbates mitochondrial dysfunction-related apoptosis.

Socio-demographic factors & adherence of newly diagnosed pulmonary tuberculosis patients to the newly introduced daily regimen: A hospital survey based follow up study

IntroductionPoor adherence to anti-tuberculosis medication is a major barrier to its global control. Patient adherence to the standard anti-TB therapy (ATT) in developing countries has been estimated to be as low as 40%. Multiple factors influencing adherence to treatment are:Economic and structural factors such as homelessness, unemployment and poverty; patient related factors like ethnicity, gender, age, knowledge about TB, cultural belief systems, mental state etc. Aims & objectivesThis study was planned with the aim to study the association between various socio-demographic factors with level of adherence to the daily regimen amongst newly diagnosed pulmonary TB patients at a tertiary care hospital in metropolitan city of Maharashtra. Additionally, we tried to determine the type of non-adherence along with reasons for it. Methodology: An interview based pre-tested and validated questionnaire was developed & used as data collection tool. Total 181 newly diagnosed, FDC naïve, drug sensitive pulmonary TB patients from DOT center of a tertiary care hospital were enrolled & interviewed for sociodemographic, treatment & adherence details. They were followed up at 2nd & 6th month of their treatment, i.e., IP & CP follow up. Their Nikshay portal data & TB treatment cards were accessed for information on treatment adherence. ResultsOut of 181 patients, 110 (60.8%) were found to be adherent whereas 71 (39.2%) were found to be non-adherent. Among those non-adherent, 64 (90.9%) had treatment gaps (intermittent missed doses) & 7 (9.9%) showed discontinuation of treatment. Majority of these patients reported personal obligations & starting to feel better as the main reason for non-adherence (p < 0.0001). The sociodemographic factors that had significant impact on level of adherence were patients’ age (p = 0.013); level of education (p = 0.035); family size (p = 0.018); family history of TB (p = 0.0001) & current smoking habit (p = 0.025). ConclusionIt is evident from the study that socio-demographic factors do have a major impact on patients’ levels of adherence to treatment. Family history of TB as well as sputum conversion at end of treatment/CP have been identified as independent risk factors among pulmonary TB patients who are non-adherent to treatment. Thus, ensuring robust availability of DBT & intensive tobacco cessation sessions for all diagnosed patients as well as strengthening system for making prophylaxis available for household & close contacts of patients can help in reducing impact of socio-demographic factors & improving adherence levels. RecommendationsIn-patient care option specifically during IP; regular dietary counseling to improve nutrition & help reduce drug side effects & use of alternate adherence technologies like facility-based DOT or Video Observed Therapy (VOT) wherever feasible can help to improve adherence levels for TB patients from all walks of life.

Model-Informed Precision Dosing of Isoniazid: Parametric Population Pharmacokinetics Model Repository.

Isoniazid (INH) is a crucial first-line anti tuberculosis (TB) drug used in adults and children. However, various factors can alter its pharmacokinetics (PK). This article aims to establish a population pharmacokinetic (popPK) models repository of INH to facilitate clinical use. A literature search was conducted until August 23, 2022, using PubMed, Embase, and Web of Science databases. We excluded published popPK studies that did not provide full model parameters or used a non-parametric method. Monte Carlo simulation works was based on RxODE. The popPK models repository was established using R. Non-compartment analysis was based on IQnca. Fourteen studies included in the repository, with eleven studies conducted in adults, three studies in children, one in pregnant women. Two-compartment with allometric scaling models were commonly used as structural models. NAT2 acetylator phenotype significantly affecting the apparent clearance (CL). Moreover, postmenstrual age (PMA) influenced the CL in pediatric patients. Monte Carlo simulation results showed that the geometric mean ratio (95% Confidence Interval, CI) of PK parameters in most studies were within the acceptable range (50.00-200.00%), pregnant patients showed a lower exposure. After a standard treatment strategy, there was a notable exposure reduction in the patients with the NAT2 RA or nonSA (IA/RA) phenotype, resulting in a 59.5% decrease in AUC0-24 and 83.2% decrease in Cmax (Infants), and a 49.3% reduction in AUC0-24 and 73.5% reduction in Cmax (Adults). Body weight and NAT2 acetylator phenotype are the most significant factors affecting the exposure of INH. PMA is a crucial factor in the pediatric population. Clinicians should consider these factors when implementing model-informed precision dosing of INH. The popPK model repository for INH will aid in optimizing treatment and enhancing patient outcomes.

Proteomic Analysis of the Mycobacterium tuberculosis Outer Membrane for Potential Implications in Uptake of Small Molecules.

Increased resistance to current antimycobacterial agents and a potential bias toward relatively hydrophobic chemical entities highlight an urgent need to understand how current anti-TB drugs enter the tubercle bacilli. While inner membrane proteins are well-studied, how small molecules cross the impenetrable outer membrane remains unknown. Here, we employed mass spectrometry-based proteomics to show that octyl-β-d-glucopyranoside selectively extracts the outer membrane proteins of Mycobacterium tuberculosis. Differentially expressed proteins between nutrient-replete and nutrient-depleted conditions were enriched to identify proteins involved in nutrient uptake. We demonstrate cell surface localization of seven new proteins using immunofluorescence and show that overexpression of the proteins LpqY and ProX leads to hypersensitivity toward streptomycin, while overexpression of SubI, SpmT, and Rv2041 exhibited higher membrane permeability, assessed through an EtBr accumulation assay. Further, proton NMR metabolomics suggests the role of six outer membrane proteins in glycerol uptake. This study identifies several outer membrane proteins that are involved in the permeation of small hydrophilic molecules and are potential targets for enhancing the uptake and efficacy of anti-TB drugs.

Benzothiadiazinone-1,1-Dioxide Carbonic Anhydrase Inhibitors Suppress the Growth of Drug-Resistant Mycobacterium tuberculosis Strains.

2H-Benzo[e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide (BTD) based carbonic anhydrase (CA) inhibitors are here explored as new anti-mycobacterial agents. The chemical features of BTD derivatives meet the criteria for a potent inhibition of β-class CA isozymes. BTD derivatives show chemical features meeting the criteria for a potent inhibition of β-class CA isozymes. Specifically, three β-CAs (MtCA1, MtCA2, and MtCA3) were identified in Mycobacterium tuberculosis and their inhibition was shown to exert an antitubercular action. BTDs derivatives 2a-q effectively inhibited the mycobacterial CAs, especially MtCA2 and MtCA3, with Ki values up to a low nanomolar range (MtCA3, Ki = 15.1-2250 nM; MtCA2, Ki = 38.1-4480 nM) and with a significant selectivity ratio over the off-target human CAs I and II. A computational study was conducted to elucidate the compound structure-activity relationship. Importantly, the most potent MtCA inhibitors demonstrated efficacy in inhibiting the growth of M. tuberculosis strains resistant to both rifampicin and isoniazid-standard reference drugs for Tuberculosis treatment.

Targeting of essential mycobacterial replication enzyme DnaG primase revealed Mitoxantrone and Vapreotide as novel mycobacterial growth inhibitors.

Tuberculosis (TB) is the second leading cause of mortality after COVID-19, with a global death toll of 1.6 million in 2021. The escalating situation of drug-resistant forms of TB has threatened the current TB management strategies. New therapeutics with novel mechanisms of action are urgently required to address the current global TB crisis. The essential mycobacterial primase DnaG with no structural homology to homo sapiens presents itself as a good candidate for drug targeting. In the present study, Mitoxantrone and Vapreotide, two FDA-approved drugs, were identified as potential anti-mycobacterial agents. Both Mitoxantrone and Vapreotide exhibit a strong Minimum Inhibitory Concentration (MIC) of ≤25μg/ml against both the virulent (M.tb-H37Rv) and avirulent (M.tb-H37Ra) strains of M.tb. Extending the validations further revealed the inhibitory potential drugs in ex vivo conditions. Leveraging the computational high-throughput multi-level docking procedures from the pool of ~2700 FDA-approved compounds, Mitoxantrone and Vapreotide were screened out as potential inhibitors of DnaG. Extensive 200 ns long all-atoms molecular dynamic simulation of DnaGDrugs complexes revealed that both drugs bind strongly and stabilize the DnaG during simulations. Reduced solvent exposure and confined motions of the active centre of DnaG upon complexation with drugs indicated that both drugs led to the closure of the active site of DnaG. From this study's findings, we propose Mitoxantrone and Vapreotide as potential anti-mycobacterial agents, with their novel mechanism of action against mycobacterial DnaG.

19 Schiff bases as antimycobacterial agents: synthesis, molecular docking and a plausible mechanism of action.

Aim: To discover novel anti-Mycobacterium tuberculosis (Mtb) drugs, 19 compounds were synthesized; their anti-Mtb effects were evaluated and mechanisms of action were preliminarily explored. Materials & methods: The compounds were synthesized and their anti-Mtb activity was elucidated using resazurin microtiter assays. The plausible target of the potential compound was investigated by microimaging techniques, gas chromatography-mass spectrometry analysis and molecular docking. Results: 19compounds inhibited Mtb growth with minimum inhibitory concentrationsranging from 1 to 32μg/ml. Compounds 1-17 showed inhibition of Mtb KatG enzyme. Compound 19, the most potent, might be an inhibitor of Pks13 polyketide synthase. Conclusion: This study suggests that 2-((6-fluoropyridin-3-yl)methylene) hydrazine-1-carbothioamide (19) is a potential anti-Mtb lead compound with a novel mechanism of action.

Concurrent Chronic Limb Threatening Ischemia and Deep Vein Thrombosis of a Limb in Patient with Systemic Lupus Erythematosus: A Case Report

AbstractConcurrent thrombus formation in both the arterial and venous systems is rare and present as a diagnostic challenge in these cases; therefore, we must explore various possible etiologies and mechanisms. Herein, we report a case of concurrent chronic limb threatening ischemia (CLTI) and deep vein thrombosis (DVT) of a limb in a patient with systemic lupus erythematosus (SLE) and chronic heart failure who underwent laboratory examinations and multimodality imaging. A 37-year-old male presented with a complaint of pain and swelling of the lower left extremity since 21 days before admission. Echocardiography showed dilated all chambers with ejection fraction, moderate-to-severe pericardial effusion, and no intracardiac shunt. Doppler ultrasound of the lower extremities showed DVT at the left mid-femoral and popliteal vein, severe stenosis at the left dorsalis pedis artery, moderate stenosis of the left popliteal, anterior, and posterior tibial arteries, and soft tissue swelling in the tibial region. Computed tomography angiography showed significant stenosis of the left popliteal, anterior, and posterior tibial arteries. The patient was diagnosed with CLTI and DVT of the left inferior extremity, heart failure, SLE, and tuberculous meningitis on antituberculosis medication. Primary amputation was performed, and the patient was discharged uneventfully.Concurrent CLTI and DVT in the same limb caused by SLE and heart failure is a rare condition. In this case, the probable causes were hypercoagulable state and vasculitis. Despite exhaustive attempts, the exact mechanism was not fully elucidated in this patient. However, we excluded other possible causes that require specific intervention, such as intracardiac shunt or phlegmasia cerulea dolens.