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Marine Drugs May 2024Tuberculosis, a persistent illness caused by , remains a significant global public health challenge. The widespread use of anti-tuberculosis drugs has resulted in the...
Tuberculosis, a persistent illness caused by , remains a significant global public health challenge. The widespread use of anti-tuberculosis drugs has resulted in the emergence of drug-resistant strains, which complicates treatment efforts. Addressing this issue is crucial and hinges on the development of new drugs that can effectively target the disease. This involves identifying novel therapeutic targets that can disrupt the bacterium's survival mechanisms in various environments such as granulomas and lesions. Citrate lyase, essential for the survival of species at lesion sites and in granulomatous conditions, is a potential target for the treatment of tuberculosis. This manuscript aimed to construct an efficient enzyme inhibitor screening platform using ultra-high performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UHPLC-QTOF MS). This system can accurately identify compounds with enzyme inhibitory activity from a library of marine terpenoids and phenolic compounds. Utilizing the screened herbal enzyme inhibitors as a starting point, we analyzed their chemical structures and skillfully built a library of marine compounds based on these structures. The results showed that all of the tested compounds from the phenolics library inhibited citrate lyase by more than 50%, and a significant portion of terpenoids also demonstrated inhibition, with these active terpenoids comprising over half of the terpenoids tested. The study underscores the potential of marine-derived phenolic and terpenoid compounds as potent inhibitors of citrate lyase, indicating a promising direction for future investigations in treating tuberculosis and associated disorders.
Topics: Tandem Mass Spectrometry; Enzyme Inhibitors; Antitubercular Agents; Mycobacterium tuberculosis; Chromatography, High Pressure Liquid; ATP Citrate (pro-S)-Lyase; Aquatic Organisms; Terpenes; Humans; Phenols; Chromatography, Liquid
PubMed: 38921556
DOI: 10.3390/md22060245 -
Globalization and Health Jun 2024The Global Drug Facility (GDF) of the Stop TB Partnership was launched in 2001 with the goal of increasing access to quality-assured tuberculosis (TB) drugs and...
BACKGROUND
The Global Drug Facility (GDF) of the Stop TB Partnership was launched in 2001 with the goal of increasing access to quality-assured tuberculosis (TB) drugs and products. We aimed to describe the TB drugs and prices available from the GDF over time and to assess trends.
METHODS
We searched the internet, including an internet archive, for past and recent GDF Product Catalogs and extracted the listed TB drugs and prices. We calculated the lowest price for the most common drug formulations assuming drugs with similar active pharmaceutical ingredients (APIs) are substitutes for each other. We assessed time trends in the TB drugs and prices offered by the GDF in univariable regressions over the longest possible period.
RESULTS
We identified 43 different GDF Product Catalogs published between November 2001 and May 2024. These product catalogs included 122 single medicines (31 APIs), 28 fixed-dose combinations (9 API combinations), and 8 patient kits (8 API regimens and other materials). The number of TB drugs listed in the GDF Product Catalog increased from 9 (8 APIs) to 55 (32 APIs). The price decreased for 17, increased for 19, and showed no trend for 12 APIs. The price of 15 (53.6%) of 28 APIs used against drug-resistant TB decreased, including the price of drugs used in new treatment regimens. The decreasing price trend was strongest for linezolid (-16.60 [95% CI: -26.35 to -6.85] percentage points [pp] per year), bedaquiline (-12.61 [95% CI: -18.00 to -7.22] pp per year), cycloserine (-11.20 [95% CI: -17.40 to -4.99] pp per year), pretomanid (-10.47 [95% CI: -15.06 to -5.89] pp per year), and rifapentine (-10.46 [95% CI: -12.86 to -8.06] pp per year). The prices of 16 (61.5%) of 23 APIs for standard drug-susceptible TB treatment increased, including rifampicin (23.70 [95% CI: 18.48 to 28.92] pp per year), isoniazid (20.95 [95% CI: 18.96 to 22.95] pp per year), ethambutol (9.85 [95% CI: 8.83 to 10.88] pp per year), and fixed-dose combinations thereof.
CONCLUSIONS
The number of TB drugs available from the GDF has substantially increased during its first 23 years of operation. The prices of most APIs for new TB treatments decreased or remained stable. The prices of most APIs for standard drug-sensitive TB treatment increased.
Topics: Humans; Antitubercular Agents; Drug Costs; Tuberculosis; Global Health
PubMed: 38918859
DOI: 10.1186/s12992-024-01047-7 -
AIDS Research and Therapy Jun 2024Tuberculosis preventive therapy is vital in caring for HIV-positive individuals, as it prevents the progression from latent tuberculosis infection to tuberculosis...
Completion of tuberculosis preventive therapy and associated factors among clients on antiretroviral therapy at Debre Berhan town health facilities, North Shoa Zone, Ethiopia.
BACKGROUND
Tuberculosis preventive therapy is vital in caring for HIV-positive individuals, as it prevents the progression from latent tuberculosis infection to tuberculosis disease. The aim of the study is to assess the completion of tuberculosis preventive therapy and associated factors among clients receiving antiretroviral therapy in Debre Berhan town, Ethiopia, in 2022.
METHOD
Institutional based cross sectional study was conducted. Random sampling methods were used to select both study participants and health facilities. Both bivariate and multivariate logistic regression analyses were performed. P-values less than 0.05 were statistically significant.
RESULT
The study found that, 83% of participants were completed tuberculosis preventive therapy. Completed tuberculosis preventive therapy was associated with no adverse drug events, taking first-line ART, and good ART adherence.
CONCLUSION
According to the Ethiopian ART guidelines, the study found a low completion rate of tuberculosis preventive therapy among HIV-positive clients on antiretroviral therapy. Factors like no adverse drug events, first-line antiretroviral regimen, and good adherence were significantly associated with completing tuberculosis preventive therapy.
Topics: Humans; Ethiopia; Male; Female; Cross-Sectional Studies; Adult; HIV Infections; Tuberculosis; Middle Aged; Medication Adherence; Antitubercular Agents; Young Adult; Anti-HIV Agents; Health Facilities; Adolescent
PubMed: 38918790
DOI: 10.1186/s12981-024-00629-0 -
Scientific Reports Jun 2024The emergence of drug-resistant Mycobacterium tuberculosis strains is a threat to global health necessitating the discovery of novel chemotherapeutic agents. Natural...
The emergence of drug-resistant Mycobacterium tuberculosis strains is a threat to global health necessitating the discovery of novel chemotherapeutic agents. Natural products drug discovery, which previously led to the discovery of rifamycins, is a valuable approach in this endeavor. Against this backdrop, we set out to investigate the in vitro antimycobacterial properties of medicinal plants from Ghana and South Africa, evaluating 36 extracts and their 252 corresponding solid phase extraction (SPE) generated fractions primarily against the non-pathogenic Mycobacterium smegmatis and Mycobacterium aurum species. The most potent fraction was further evaluated in vitro against infectious M. tuberculosis strain. Crinum asiaticum (bulb) (Amaryllidaceae) emerged as the most potent plant species with specific fractions showing exceptional, near equipotent activity against the non-pathogenic Mycobacterium species (0.39 µg/ml ≤ MIC ≤ 25 µg/ml) with one fraction being moderately active (MIC = 32.6 µg/ml) against M. tuberculosis. Metabolomic analysis led to the identification of eight compounds predicted to be active against M. smegmatis and M. aurum. In conclusion, from our comprehensive study, we generated data which provided an insight into the antimycobacterial properties of Ghanaian and South African plants. Future work will be focused on the isolation and evaluation of the compounds predicted to be active.
Topics: Plants, Medicinal; Microbial Sensitivity Tests; South Africa; Plant Extracts; Ghana; Mycobacterium tuberculosis; Antitubercular Agents; Mycobacterium; Mycobacterium smegmatis; Humans; Anti-Bacterial Agents
PubMed: 38918410
DOI: 10.1038/s41598-024-65369-7 -
International Journal of... Apr 2024Bacille Calmette-Guérin (BCG) is a live-attenuated vaccine routinely administered to newborns to prevent severe forms of tuberculosis (TB) in TB-endemic countries.... (Review)
Review
Infantile Disseminated Bacille Calmette-Guérin Disease with Hemophagocytosis and Mimicking Juvenile Myelomonocytic Leukemia: A Case Report with Concise Literature Review.
Bacille Calmette-Guérin (BCG) is a live-attenuated vaccine routinely administered to newborns to prevent severe forms of tuberculosis (TB) in TB-endemic countries. Disseminated BCG vaccine disease is a classic feature of children with human immunodeficiency virus (HIV) or primary immunodeficiency disorders (PIDs) and is associated with high mortality. We report a case of a 6-month-old infant with disseminated BCG disease and hemophagocytic lymphohistiocytosis mimicking juvenile myelomonocytic leukemia with no demonstrable features of HIV or PID even after extensive laboratory work-up and succumbed to progressive disease. Disseminated BCG disease is a rare and potentially fatal complication of BCG vaccine, and prompt immunological evaluation complemented by initiation of 4-drug antitubercular therapy and definitive treatment with antiretroviral therapy or hematopoietic stem cell transplant is warranted.
Topics: Humans; Leukemia, Myelomonocytic, Juvenile; Infant; Lymphohistiocytosis, Hemophagocytic; BCG Vaccine; Tuberculosis; Diagnosis, Differential; Fatal Outcome; Male; Mycobacterium bovis; Antitubercular Agents
PubMed: 38916394
DOI: 10.4103/ijmy.ijmy_48_24 -
International Journal of... Apr 2024Pharmacogenetic research has led to significant progress in understanding how genetic factors influence drug response in tuberculosis (TB) treatment. One ongoing...
BACKGROUND
Pharmacogenetic research has led to significant progress in understanding how genetic factors influence drug response in tuberculosis (TB) treatment. One ongoing challenge is the variable occurrence of adverse drug reactions in some TB patients. Previous studies have indicated that genetic variations in the N-acetyltransferase 2 (NAT2) and solute carrier organic anion transporter family member 1B1 (SLCO1B1) genes can impact the blood concentrations of the first-line anti-TB drugs isoniazid (INH) and rifampicin (RIF), respectively. This study aimed to investigate the influence of pharmacogenetic markers in the NAT2 and SLCO1B1 genes on TB treatment outcomes using whole-exome sequencing (WES) analysis.
METHODS
DNA samples were collected from 30 healthy Iranian adults aged 18-40 years. The allelic frequencies of single-nucleotide polymorphisms (SNPs) in the NAT2 and SLCO1B1 genes were determined through WES.
RESULTS
Seven frequent SNPs were identified in the NAT2 gene (rs1041983, rs1801280, rs1799929, rs1799930, rs1208, rs1799931, rs2552), along with 16 frequent SNPs in the SLCO1B1 gene (rs2306283, rs11045818, rs11045819, rs4149056, rs4149057, rs2291075, rs201722521, rs11045852, rs11045854, rs756393362, rs11045859, rs74064211, rs201556175, rs34671512, rs71581985, rs4149085).
CONCLUSION
Genetic variations in NAT2 and SLCO1B1 can affect the metabolism of INH and RIF, respectively. A better understanding of the pharmacogenetic profile in the study population may facilitate the design of more personalized and effective TB treatment strategies. Further research is needed to directly correlate these genetic markers with clinical outcomes in TB patients.
Topics: Humans; Arylamine N-Acetyltransferase; Liver-Specific Organic Anion Transporter 1; Adult; Antitubercular Agents; Male; Young Adult; Mycobacterium tuberculosis; Polymorphism, Single Nucleotide; Rifampin; Adolescent; Female; Isoniazid; Iran; Tuberculosis; Gene Frequency; Exome Sequencing; Pharmacogenomic Testing; Pharmacogenetics
PubMed: 38916393
DOI: 10.4103/ijmy.ijmy_106_24 -
International Journal of... Apr 2024Tuberculosis (TB), a global infectious threat, has seen a concerning rise in aminoglycoside-resistant Mycobacterium tuberculosis (M.tb) strains. The potential role of... (Comparative Study)
Comparative Study
Comparative Proteomic Analysis of Capsule Proteins in Aminoglycoside-Resistant and Sensitive Mycobacterium tuberculosis Clinical Isolates: Unraveling Potential Drug Targets.
BACKGROUND
Tuberculosis (TB), a global infectious threat, has seen a concerning rise in aminoglycoside-resistant Mycobacterium tuberculosis (M.tb) strains. The potential role of capsule proteins remains largely unexplored. This layer acts as the primary barrier for tubercle bacilli, attempting to infiltrate host cells and subsequent disease development.
METHODS
The study aims to bridge this gap by investigating the differentially expressed capsule proteins in aminoglycoside-resistant M.tb clinical isolates compared with drug-sensitive isolates employing two-dimensional gel electrophoresis, mass spectrometry, and bioinformatic approaches.
RESULTS
We identified eight proteins that exhibited significant upregulation in aminoglycoside-resistant isolates. Protein Rv3029c and Rv2110c were associated with intermediary metabolism and respiration; Rv2462c with cell wall and cell processes; Rv3804c with lipid metabolism; Rv2416c and Rv2623 with virulence and detoxification/adaptation; Rv0020c with regulatory functions; and Rv0639 with information pathways. Notably, the Group-based Prediction System for Prokaryotic Ubiquitin-like Protein (GPS-PUP) algorithm identified potential pupylation sites within all proteins except Rv3804c. Interactome analysis using the STRING 12.0 database revealed potential interactive partners for these proteins, suggesting their involvement in aminoglycoside resistance. Molecular docking studies revealed suitable binding between amikacin and kanamycin drugs with Rv2462c, Rv3804c, and Rv2623 proteins.
CONCLUSION
As a result, our findings illustrate the multifaceted nature of aminoglycoside resistance in M.tb and the importance of understanding how capsule proteins play a role in counteracting drug efficacy. Identifying the role of these proteins in drug resistance is crucial for developing more effective treatments and diagnostics for TB.
Topics: Mycobacterium tuberculosis; Humans; Proteomics; Bacterial Proteins; Aminoglycosides; Drug Resistance, Bacterial; Bacterial Capsules; Antitubercular Agents; Microbial Sensitivity Tests; Computational Biology; Electrophoresis, Gel, Two-Dimensional; Tuberculosis
PubMed: 38916392
DOI: 10.4103/ijmy.ijmy_47_24 -
International Journal of... Apr 2024On a global scale, India holds the distinction of having the greatest number of tuberculosis (TB) cases caused by Mycobacterium tuberculosis (MTB) complex. The study... (Comparative Study)
Comparative Study
BACKGROUND
On a global scale, India holds the distinction of having the greatest number of tuberculosis (TB) cases caused by Mycobacterium tuberculosis (MTB) complex. The study aimed at evaluating the sensitivity, specificity, accuracy, cost, rapidity, and feasibility of the performance of the colorimetric nitrate reductase-based antibiotic susceptibility (CONRAS) test against the indirect proportion method (IPM) on Lowenstein-Jensen media as the gold standard.
METHODS
A comparative cross-sectional study was performed on 51 MTB isolates. Fresh subcultures were used for drug susceptibility testing by IPM on the Lowenstein-Jensen medium and the CONRAS method in liquid medium. Quality control for drug susceptibility testing was done using a known sensitive strain of MTB (H37Rv) and strains resistant to both isoniazid (INH) and rifampicin (RIF) - multidrug-resistant (MDR), mono-resistant to RIF, streptomycin (STM), and ethambutol (EMB). Statistical analysis was performed using MedCalc software (Version 20.027).
RESULTS
CONRAS, carried out in microfuge tubes, was cost-efficient and easy to perform/interpret with most results being available in 10 days compared to 42 days in the case of IPM. The sensitivity, specificity, and accuracy of RIF and INH were 100%, 97.37%, and 98.04 and 93.33%, 97.59%, and 96.08%, respectively, which translates into an almost perfect agreement between the two methods as indicated by κ value of 0.905 and 0.949, respectively, for the two drugs. The performance of CONRAS was less satisfactory for STM and EMB when compared to IPM.
CONCLUSIONS
CONRAS may serve as a useful test for the detection of MDR-TB because of its accuracy, low cost, ease of performance/interpretation, and rapidity when compared to IPM on LJ medium. It does not involve the use of expensive reagents and equipment, as is the case with molecular methods like GeneXpert and line probe assay, making it a suitable option for the detection of MDR-TB in resource-poor settings.
Topics: Nitrate Reductase; Mycobacterium tuberculosis; Colorimetry; Microbial Sensitivity Tests; Antitubercular Agents; Humans; Cross-Sectional Studies; Sensitivity and Specificity; Culture Media; India; Tuberculosis, Multidrug-Resistant
PubMed: 38916391
DOI: 10.4103/ijmy.ijmy_69_24 -
International Journal of... Apr 2024Chronic kidney disease (CKD) patients are at a high risk of tuberculosis (TB), with a relative risk of developing active TB of 10%-25%. Similarly, glomerular disease...
BACKGROUND
Chronic kidney disease (CKD) patients are at a high risk of tuberculosis (TB), with a relative risk of developing active TB of 10%-25%. Similarly, glomerular disease increases the risk of TB due to diminished glomerular filtration rate, proteinuria, and immunosuppression use. Further, the first-line anti-TB drugs are associated with acute kidney injury (AKI) even in patients with normal kidney functions.
METHODS
We retrospectively identified 10 patients hospitalized with unusual adverse effects of antituberculosis therapy (ATT) from 2013 to 2022.
RESULTS
We found three cases of AKI caused by rifampicin: acute interstitial nephritis, crescentic glomerulonephritis, and heme pigment-induced acute tubular necrosis. We observed rifampicin-induced accelerated hypertension and thrombocytopenia in two patients on maintenance hemodialysis. Isoniazid caused pancreatitis and cerebellitis in two CKD patients, respectively. In a CKD patient, we detected acute gout secondary to pyrazinamide-induced reduced uric acid excretion. We also observed cases of drug rash with eosinophilia and systemic symptoms and hypercalcemia due to immune reconstitution inflammatory syndrome in patients with glomerular disease on ATT. Immediate discontinuation of the offending drug, along with specific and supportive management, led to a recovery in all cases.
CONCLUSION
The adverse effects of ATT may be unusually severe and varied in kidney patients due to decreased renal elimination. Early recognition of these adverse effects and timely discontinuation of the offending drug is essential to limit morbidity and mortality.
Topics: Humans; Antitubercular Agents; Male; Retrospective Studies; Female; Middle Aged; Acute Kidney Injury; Aged; Adult; Renal Insufficiency, Chronic; Rifampin; Isoniazid; Nephritis, Interstitial; Tuberculosis; Pyrazinamide; Glomerulonephritis; Immune Reconstitution Inflammatory Syndrome
PubMed: 38916390
DOI: 10.4103/ijmy.ijmy_33_24 -
International Journal of... Apr 2024GeneXpert Mycobacterium tuberculosis/rifampicin (MTB/RIF) is a conceptually helpful tool for establishing tuberculosis (TB) disease. Negative results from the GeneXpert...
OBJECTIVE
GeneXpert Mycobacterium tuberculosis/rifampicin (MTB/RIF) is a conceptually helpful tool for establishing tuberculosis (TB) disease. Negative results from the GeneXpert test do not exclude the possibility of diagnosing non-tuberculous mycobacteria lung disease (NTMLD) as a chronic pulmonary disease. When a patient is diagnosed on a clinical basis, and there is no bacteriological evidence of TB, it is necessary to consider NTM as one of the causes of disease with TB-like symptoms. The prevalence of non-tuberculous mycobacteria (NTM) disease is rising globally, but its diagnosis is still delayed and often misdiagnosed as multidrug-resistant TB (MDR-TB). This study highlights the implication of negative GeneXpert MTB/RIF results in suspected TB patients who conducted mycobacteria culture and detected the incidence of NTMLD.
METHODS
In this experimental study, the performance of GeneXpert MTB/RIF-negative results with those of mycobacteria cultures and lung abnormalities among suspected TB patients in a referral hospital in Indonesia were evaluated. From January to August 2022, 100 sputum samples from suspected chronic pulmonary TB patients with GeneXpert MTB/RIF assay-negative results were cultured in Lowenstein-Jensen medium, and the implication among negative GeneXpert result MTB/RIF assay.
RESULTS
7% were confirmed to have MTB and 1% had NTM by culture assay. Moreover, 34% were diagnosed with clinical TB and treated with anti-TB drugs.
CONCLUSION
For patients with negative assay results of GeneXpert MTB/RIF regarding clinically suspected chronic TB infection, further diagnostic tests to determine the causative agents of the lung abnormalities should be carried out.
Topics: Humans; Mycobacterium tuberculosis; Rifampin; Male; Sputum; Female; Adult; Middle Aged; Indonesia; Tuberculosis, Pulmonary; Mycobacterium Infections, Nontuberculous; Tuberculosis, Multidrug-Resistant; Nontuberculous Mycobacteria; Aged; Young Adult
PubMed: 38916385
DOI: 10.4103/ijmy.ijmy_100_24