Tuberculosis Drug Research Articles

Ajoene: a natural compound with enhanced antimycobacterial and antibiofilm properties mediated by efflux pump modulation and ROS generation against M. Smegmatis.

Tuberculosis (TB) continues to be a primary worldwide health concern due to relatively ineffective treatments. The prolonged duration of conventional antibiotic therapy warrants innovative approaches to shorten treatment courses. In response to challenges, the study explores potential of Ajoene, a naturally occurring garlic extract-derived compound, for potential TB treatment. Mycobacterium smegmatis as a model organism for M. tuberculosis (M. tb) to investigate Ajoene's efficiency. In vitro techniques like antimicrobial susceptibility, antibiofilm, EtBr accumulation assay, and ROS assay evaluate the potency of Ajoene and conventional TB drugs against Mycobacterium smegmatis. An in-silico study also investigated the interaction between Ajoene and quorum-sensing proteins, specifically regX3, MSMEG_5244, and MSMEG_3944, which are involved in biofilm formation and sliding activity. In vitro findings revealed that Ajoene exhibited significant antibacterial activity by inhibiting growth and showing bactericidal effects. It also demonstrated additive interactions with common antibiotics such as Isoniazid and Rifampicin. Furthermore, Ajoene demonstrated a comparative interaction with commonly used antibiotics, such as Isoniazid and Rifampicin, and reduced M. smegmatis motility, both alone and in combination with these antibiotics. In silico analysis shows that Ajoene exhibited a higher binding affinity with regX3, a protein orthologous to the regX3 gene in M.tb. Ajoene also demonstrated consistent antibiofilm effects, particularly when combined synergistically with Isoniazid and Rifampicin. Mechanistic investigations demonstrated Ajoene's potential to inhibit efflux pumps and promote ROS generation in bacteria, suggesting a potential direct killing mechanism. Collectively, the findings emphasize Ajoene's effectiveness as a novel antimycobacterial and antibiofilm molecule for TB treatment.

Role of Nutraceuticals in Treating Erectile Dysfunction via Inhibition of Phosphodiesterase-5 Enzyme: A Mini Review.

Erectile Dysfunction (ED) is a prevalent sexual health condition affecting a significant portion of the male population worldwide. The conventional therapeutic approaches for ED often involve the use of pharmaceutical agents targeting the phosphodiesterase-5 (PDE5) enzyme. Currently, treatment with PDE-5 inhibitors is the standard approach for ED, and four PDE-5 inhibitors, namely sildenafil, vardenafil, tadalafil, and avanafil, are in use. However, these pharmaceutical interventions may be associated with adverse effects and limitations. As a result, there has been a growing interest in exploring alternative and complementary treatment options for ED, such as nutraceuticals, which are bioactive compounds derived from natural sources. Nutraceuticals, which include vitamins, minerals, herbs, and other dietary supplements, have gained popularity for their potential health benefits. Certain nutraceuticals have demonstrated the ability to modulate various physiological pathways, including those involved in erectile function. A notable mechanism of action is the inhibition of the PDE5 enzyme, which plays a pivotal role in the regulation of cGMP levels. By inhibiting PDE5, nutraceuticals can promote the accumulation of cGMP, leading to enhanced penile blood flow and improved erectile function. A comprehensive analysis of the literature showcases various nutraceutical agents, including plant-derived compounds like flavonoids, polyphenols, and amino acids which have exhibited PDE5 inhibitory effects. Mechanistic insights into their action involve modulation of NO release, cGMP elevation, and relaxation of penile smooth muscles, all critical factors for achieving and sustaining erections. This review focuses on elucidating the role of nutraceuticals in treating erectile dysfunction through the inhibition of the PDE5 enzyme.

Toxoplasma gondii macrophage migration inhibitory factor shows anti-Mycobacterium tuberculosis potential via AZIN1/STAT1 interaction.

Mycobacterium tuberculosis (MTB) is a pathogenic bacterium, belonging to the family Mycobacteriaceae, that causes tuberculosis (TB). Toxoplasma gondii macrophage migration inhibitory factor (TgMIF), a protein homolog of macrophage migration inhibitory factor, has been explored for its potential to modulate immune responses during MTB infections. We observed that TgMIF that interacts with CD74, antizyme inhibitor 1 (AZIN1), and signal transducer and activator of transcription 1 (STAT1) modulates endocytosis, restoration of mitochondrial function, and macrophage polarization, respectively. These interactions promote therapeutic efficacy in mice infected with MTB, thereby presenting a potential route to host-directed therapy development. Furthermore, TgMIF, in combination with first-line TB drugs, significantly inhibited drug-resistant MTB strains, including multidrug-resistant TB. These results demonstrate that TgMIF is potentially a multifaceted therapeutic agent against TB, acting through immune modulation, enhancement of mitochondrial function, and dependent on STAT1 and AZIN1 pathways.

Targeted next-generation sequencing - a promising approach in the diagnosis of Mycobacterium tuberculosis and drug resistance.

Targeted next-generation sequencing (tNGS) offers a high-throughput, culture-independent approach that delivers a comprehensive resistance profile in a significantly shorter turn-around time, making it promising in enhancing tuberculosis (TB) diagnosis and informing treatment decisions. This study aims to evaluate the performance of tNGS in the TB diagnosis and drug resistance detection of Mycobacterium tuberculosis (MTB) using MTB clinical isolates and bronchoalveolar lavage fluid (BALF) samples. A total of 143 MTB clinical isolates were assessed, tNGS, phenotypic antimicrobial susceptibility testing (AST), and AST based on whole genome sequencing (WGS) exhibited high concordance rates, averaging 95.10% and 97.05%. Among 158 BALF samples, culture, Xpert MTB/RIF, and tNGS reported 29, 70 and 111 positives, respectively. In the confirmed cases with etiological evidence (smears, cultures, or molecular test), the positive rate of tNGS (73/83, 87.95%) was higher than that of Xpert MTB (67/83, 80.72%). Additionally, 45% (27/60) of clinically diagnosed cases (with imaging or immunological evidence) were positive for tNGS. Further validation on the discrepant results between tNGS and Xpert MTB/RIF with droplet digital PCR (ddPCR) yielded 35 positives, tNGS detected all, and Xpert MTB/RIF only identified 6 positives. In conclusion, tNGS demonstrates robust and rapid performance in the identification of MTB and its associated drug resistance, and can be directly applied to clinical samples, positioning it as a promising approach for laboratory testing of tuberculosis.

Engineered Mycobacteriophage TM4::GeNL Rapidly Determines Bedaquiline, Pretomanid, Linezolid, Rifampicin, and Clofazimine Sensitivity in Mycobacterium tuberculosis Clinical Isolates.

Drug-resistant tuberculosis is a growing public health threat, and early characterization of the resistance phenotype is essential for guiding treatment and mitigating the high mortality associated with the disease. However, the slow growth rate of Mycobacterium tuberculosis, the causative agent of tuberculosis, necessitates several weeks for conventional culture-dependent drug susceptibility testing (DST). In addition, there are no widely available molecular diagnostic assays for evaluating resistance to newer tuberculosis drugs or drugs with complex resistance mechanisms. We have developed a luciferase-based reporter mycobacteriophage assay that can determine drug resistance within 48 hours. We engineered the TM4 mycobacteriophage to express green enhanced nanoluciferase (GeNL) cassette and optimized DST for bedaquiline, pretomanid, linezolid, clofazimine, and rifampicin using clinical M. tuberculosis isolates. To assess the feasibility of this assay, we conducted a proof-of-principle study using 53 clinical M. tuberculosis isolates. TM4::GeNL phage DST effectively distinguished between sensitive and resistant isolates for bedaquiline and rifampicin at a concentration of 0.125 μg/mL. Optimal differentiation between sensitive and resistant isolates for pretomanid, clofazimine, and linezolid was achieved at concentrations of 0.5 μg/mL, 0.25 μg/mL, and 1 μg/mL, respectively. Additionally, TM4::GeNL DST identified low-level rifampicin resistance in clinical isolates even though they were classified as sensitive by Mycobacteria Growth Indicator Tube DST. TM4::GeNL reporter phage DST offers a rapid method to identify M. tuberculosis drug resistance, including resistance to newer tuberculosis drugs.

Panorama dos principais estudos clínicos sobre medicamentos contra tuberculose no Brasil e no mundo

Introduction: This article provides a comprehensive overview of tuberculosis (TB) drug clinical trials conducted in Brazil and globally. TB is highlighted as one of the leading lethal infectious diseases, facing the growing challenge of drug resistance. Objective: The study aims to map recent advances and identify gaps and challenges in the search for effective treatments for TB, emphasizing Brazil’s contribution, which is known for its research in tropical diseases. Method: An analysis of clinical trials related to TB was conducted, focusing on the geographical diversity of the studies and the intersectoral collaboration between governments, academic institutions, and non-governmental organizations. The survey covered research at both national and international levels. Results: The results indicate a significant increase in the number of clinical trials, reflecting a growing interest and investment in research and development (R&D) aimed at combating TB. Regions with high disease incidence have received special attention. Collaboration between different sectors has been crucial in promoting progress. Conclusions: Despite the advances, the study underscores important challenges, such as the need for more R&D investments and the urgency of public policies to facilitate access to new drugs. The article highlights the importance of continuous and collaborative efforts in developing safe and accessible treatments, as well as the effective integration of innovations into the healthcare system, with special attention to vulnerable populations.

Synergistic oral beta-lactam combinations for treating tuberculosis.

The enormous burden of tuberculosis (TB) worldwide is a major challenge to human health, but the costs and risks associated with novel drug discovery have limited treatment options for patients. Repurposing existing antimicrobial drugs offers a promising avenue to expand TB treatment possibilities. This study aimed to explore the activity and synergy of beta-lactams in combination with a beta-lactamase inhibitor, which have been underutilised in TB treatment to date. Based on inhibitory concentration, oral bioavailability and commercial availability, seven beta-lactams (cefadroxil, tebipenem, cephradine, cephalexin, cefdinir, penicillin V, flucloxacillin), two beta-lactamase inhibitors (avibactam and clavulanate), and three second-line TB drugs (moxifloxacin, levofloxacin and linezolid) were selected for combination in vitro testing against Mycobacterium tuberculosis H37Rv. Resazurin assays and colony forming unit (CFU) enumeration were used to quantify drug efficacy, Chou-Talalay calculations were performed to identify drug synergy and Chou-Martin calculations were performed to quantify drug dose reduction index (DRI). The order of activity of beta-lactams was cefadroxil>tebipenem>cephradine>cephalexin>cefdinir>penicillin V>flucloxacillin. The addition of clavulanate improved beta-lactam activity to a greater degree than the addition of avibactam. As a result, avibactam was excluded from further investigations, which focused on clavulanate. Synergy was demonstrated for cefdinir/cephradine, cefadroxil/tebipenem, cefadroxil/penicillin V, cefadroxil/cefdinir, cephalexin/tebipenem, cephalexin/penicillin V, cephalexin/cefdinir, cephalexin/cephradine and cefadroxil/cephalexin, all with clavulanate. However, combining beta-lactams with moxifloxacin, levofloxacin or linezolid resulted in antagonistic effects, except for the combinations of penicillin V/levofloxacin, penicillin V/moxifloxacin and cefdinir/moxifloxacin. Beta-lactam synergy may provide viable combination therapies for the treatment of TB.

Quantification of MDR-TB drug JBD0131 and its metabolite in plasma via UPLC-MS/MS: application in first-in-human study.

Aim: JBD0131, a novel anti-multidrug-resistant tuberculosis (MDR-TB) drug, can target and inhibit the synthesis of mycolic acids, which are crucial components of the cell wall of the Mycobacterium tuberculosis complex. To support the results of this clinical trial in healthy subjects, development of a specific and accurate quantification method for detecting JBD0131 and its metabolite DM131 in human plasma is needed.Materials & methods: Samples with prior added stabilizer were pretreated by protein precipitation method and the extracts weresubjected to ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The m/z transitions for the precursor/product ion pairs were 402.1/273 for JBD0131, 333.1/273 for DM131 and 386.1/257 for the internal standard (IS).Results: This method showed good linearity from 1 to 2000ng/ml for JBD0131 and 0.25 to 500ng/ml for DM131 and was validated in terms of selectivity, linearity, accuracy, precision, matrix effect, recovery of pretreament and stability.Conclusion: This method was sensitive and specific for measuring the plasma concentrations of JBD0131 and its metabolites. And it was applied for the investigation of the pharmacokinetics of JBD0131 and DM131 in a clinical trial.

An Update to Novel Therapeutic Options for Combating Tuberculosis: Challenges and Future Prospectives.

Drug repurposing is an ongoing and clever strategy that is being developed to eradicate tuberculosis amid challenges, of which one of the major challenges is the resistance developed towards antibiotics used in standard directly observed treatment, short-course regimen. Surpassing the challenges in developing anti-tuberculous drugs, some novel host-directed therapies, repurposed drugs, and drugs with novel targets are being studied, and few are being approved too. After almost 4 decades since the approval of rifampicin as a potent drug for drugsusceptible tuberculosis, the first drug to be approved for drug-resistant tuberculosis is bedaquiline. Ever since the urge to drug discovery has been at a brisk as this milestone in tuberculosis treatment has provoked the hunt for novel targets in tuberculosis. Host-directed therapy and repurposed drugs are in trend as their pharmacological and toxicological properties have already been researched for some other diseases making the trial facile. This review discusses the remonstrance faced by researchers in developing a drug candidate with a novel target, the furtherance in tuberculosis research, novel anti-tuberculosis agents approved so far, and candidates on trial including the host-directed therapy, repurposed drug and drug combinations that may prove to be potential in treating tuberculosis soon, aiming to augment the awareness in this context to the imminent researchers.

Relationship between knowledge and adherence to use of TB drugs in adults in Idaman Banjarbaru Hospital

Background: Worldwide, tuberculosis (TB) is the disease that causes the highest mortality rate. One of the causes is the bacteria Mycobacterium Tuberculosis. Knowledge and adherence are very important in TB treatment to achieve therapeutic success. Objectives: This study aims to see the relationship between the level of knowledge and adherence to taking medication for adult TB patients at Idaman Banjarbaru Hospital. Methods: This type of research is descriptive research with a cross-sectional research design prospectively taken in March - June 2023. The number of patients was 42 people using the total sampling technique. Data were collected through an online questionnaire and then analyzed using the SPSS Fisher Exact test with a 95% confidence level. Results: The results showed that patients had a good level of knowledge of as many as 32 people (76.2%) and had less knowledge of as many as 10 people (23.8%). The value of patient compliance in taking medication was 29 people (69%), and disobedient as many as 13 people (31%). Conclusion: The results of the statistical analysis concluded that there was a relationship between knowledge and compliance with taking medication in TB patients at Idaman Banjarbaru Hospital (p < 0.05).

Drug repurposing: An antidiabetic drug Ipragliflozin as Mycobacterium tuberculosis sirtuin-like protein inhibitor that synergizes with anti-tuberculosis drug isoniazid.

The surge of drug-resistant Mycobacterium tuberculosis (DR-TB) impedes the World Health Organization's efforts in ending TB and calls for new therapeutic formulations. M. tuberculosis sirtuin-like protein Rv1151c is a bifunctional enzyme with both deacetylation and desuccinylation activities, which plays an important role in M. tuberculosis drug resistance and stress responses. Thus, it appears to be a promising target for the development of new TB therapeutics. In this study, we screened 31,057 ligand compounds from seven compound libraries in silico to identify inhibitors of Rv1151c. Ipragliflozin can bind to Rv1151c and interact stably. Ipragliflozin can change the acylation level of M. tuberculosis by inhibiting Rv1151c and effectively inhibit the growth of M. tuberculosis H37Rv and M. smegmatis. It can potentiate the first-front anti-TB drug isoniazid. As an antidiabetic drug, Ipragliflozin can be potentially included in the regimen to treat diabetes-tuberculosis comorbidity.

Evaluating culture-free targeted next-generation sequencing for diagnosing drug-resistant tuberculosis: a multicentre clinical study of two end-to-end commercial workflows.

Drug-resistant tuberculosis remains a major obstacle in ending the global tuberculosis epidemic. Deployment of molecular tools for comprehensive drug resistance profiling is imperative for successful detection and characterisation of tuberculosis drug resistance. We aimed to assess the diagnostic accuracy of a new class of molecular diagnostics for drug-resistant tuberculosis. We conducted a prospective, cross-sectional, multicentre clinical evaluation of the performance of two targeted next-generation sequencing (tNGS) assays for drug-resistant tuberculosis at reference laboratories in three countries (Georgia, India, and South Africa) to assess diagnostic accuracy and index test failure rates. Eligible participants were aged 18 years or older, with molecularly confirmed pulmonary tuberculosis, and at risk for rifampicin-resistant tuberculosis. Sensitivity and specificity for both tNGS index tests (GenoScreen Deeplex Myc-TB and Oxford Nanopore Technologies [ONT] Tuberculosis Drug Resistance Test) were calculated for rifampicin, isoniazid, fluoroquinolones (moxifloxacin, levofloxacin), second line-injectables (amikacin, kanamycin, capreomycin), pyrazinamide, bedaquiline, linezolid, clofazimine, ethambutol, and streptomycin against a composite reference standard of phenotypic drug susceptibility testing and whole-genome sequencing. Between April 1, 2021, and June 30, 2022, 832 individuals were invited to participate in the study, of whom 720 were included in the final analysis (212, 376, and 132 participants in Georgia, India, and South Africa, respectively). Of 720 clinical sediment samples evaluated, 658 (91%) and 684 (95%) produced complete or partial results on the GenoScreen and ONT tNGS workflows, respectively, with 593 (96%) and 603 (98%) of 616 smear-positive samples producing tNGS sequence data. Both workflows had sensitivities and specificities of more than 95% for rifampicin and isoniazid, and high accuracy for fluoroquinolones (sensitivity approximately ≥94%) and second line-injectables (sensitivity 80%) compared with the composite reference standard. Importantly, these assays also detected mutations associated with resistance to critical new and repurposed drugs (bedaquiline, linezolid) not currently detectable by any other WHO-recommended rapid diagnostics on the market. We note that the current format of assays have low sensitivity (≤50%) for linezolid and more work on mutations associated with drug resistance is needed. This multicentre evaluation demonstrates that culture-free tNGS can provide accurate sequencing results for detection and characterisation of drug resistance from Mycobacterium tuberculosis clinical sediment samples for timely, comprehensive profiling of drug-resistant tuberculosis. Unitaid.

Варианты генов Mycobacterium tuberculosis, ассоциированные с лекарственной устойчивостью к фторхинолонам (обзор литературы)

Background: The spread of M. tuberculosis drug resistance to fluoroquinolones poses a threat to their long-term clinical efficacy. Understanding the mechanisms of formation of drug resistance to fluoroquinolones, based on information on genes associated with drug resistance of M. tuberculosis, is important for optimizing TB chemotherapy regimens. The aim of the study: To study the available literature data on the most significant variants of M. tuberculosis genes associated with drug resistance to fluoroquinolones. Materials and methods: To achieve this goal, the task was to analyze the sources of domestic and foreign literature on this priority issue over the past 5 years. The databases of scientific electronic libraries PubMed, Elibriary were used. Results: Mycobacterial resistance to fluoroquinolones is associated with mutations in the gyrA and gyrB genes, encoding the GyrA and GyrB subunits of DNA gyrase, the main target of fluoroquinolones. In the fluoroquinolone-binding pocket of the “DNA-gyrase + DNA” catalytic center, the fluoroquinolone molecule is supported by the gyrA and gyrB regions, which determine resistance to fluoroquinolones (QRDR-A and QRDR-B). Modification of any of the constituent fragments of these regions affects the level of resistance to fluoroquinolones. Small quinolone molecules (nalidixic acid) have a high MIC against Mtb and other bacteria, while larger PC molecules (sparfloxacin, sitafloxacin, gatifloxacin, levofloxacin and moxifloxacin) are tightly adjacent to the fluoroquinolone-binding pocket and have a lower MIC. Modification of the DNA structure can change the spatial structure of the pocket itself, which leads to destabilization of the fluoroquinolone inside it. Thus, the presence of heteroresistance of the tuberculosis pathogen to fluoroquinolones indicates the active development of its resistance to this group of drugs in modern conditions. Conclusion: Analysis of modern studies shows the dependence of drug resistance of mycobacteria on fluoroquinolone compounds, while most often resistance to a decrease in the concentration of fluoroquinolones is associated with substitutions in the gyrB gene, as well as mutations in the gyrA gene. It has also been established that in addition to the main studied regions of the gyrA and gyrB genes associated with phenotypic drug resistance to fluoroquinols, there are regions that have not been sufficiently studied so far. These areas cannot be diagnosed in the clinical work of bacteriological laboratories of anti-tuberculosis institutions.

Targeting CCRL2 enhances therapeutic outcomes in a tuberculosis mouse model.

Tuberculosis (TB) remains among the leading infectious causes of death. Due to the limited number of antimicrobials in the TB drug discovery pipeline, interest has developed in host-directed approaches to improve TB treatment outcomes. C-C motif chemokine-like receptor 2 (CCRL2) is a unique seven-transmembrane domain receptor that is upregulated by inflammatory signals and mediates leucocyte migration. However, little is known about its role in the setting of TB infection. Here, we show that Mycobacterium tuberculosis (Mtb) infection increases CCRL2 protein expression in macrophages and in mouse lungs. To target selectively CCRL2-expressing cells in vivo, we developed a novel mouse anti-CCRL2 antibody-drug conjugate (ADC) linked with the cytotoxic drug SG3249. We tested its adjunctive therapeutic efficacy against TB when combined with the first-line regimen for drug-susceptible TB (isoniazid, rifampin, pyrazinamide, ethambutol; RHZE). The anti-CCRL2 ADC treatment potentiated RHZE efficacy in Mtb-infected mice and decreased gross lung inflammation. CCRL2 expression in lung dendritic cells and alveolar macrophages was lower in mice receiving anti-CCRL2 ADC treatment + RHZE compared to those receiving RHZE alone or the control group, although the total innate cell populations did not differ across treatment groups. Interestingly, neutrophils were completely absent in the anti-CCRL2 ADC treatment + RHZE group, unlike in the other treatment groups. IFN-γ+ and IL17-Α+ T-cell responses, which are associated with optimal TB control, were also elevated in the anti-CCRL2 ADC treatment + RHZE group. Collectively, our findings suggest that CCRL2-targeting approaches may improve TB treatment outcomes, possibly through selective killing of Mtb-infected innate immune cells.

Are Ethiopian health facilities providing diabetes services capable of managing tuberculosis? Policy implications for introducing diabetes and tuberculosis collaborative care

ObjectiveThis study aimed to assess the availability and preparedness of health facilities offering diabetes mellitus (DM) to manage tuberculosis (TB) in Ethiopia.DesignSecondary data analysis of institution-based cross-sectional national survey data.SettingData...

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

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). Newly diagnosed pulmonary TB patients aged 18-60years with or without DM were included in the study. Group I (n = 20) included patients with TB, whereas group II (n = 20) included patients withboth 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. 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 underthe 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. 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. CTRI/2021/08/035578 dated 11/08/2021.

The Relationship Between Compliance in Taking Anti Tuberculosis Drugs and the Results of Acid-Fast Bacteria (AFB) Examination as an Indicator of Recovery of TB Patients in Tanjung Pinang City in 2022-2023

Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis with a treatment period of 6 to 8 months. Mycobacterium tuberculosis can become germ resistant or multidrug resistance (MDR) if you do not comply in taking anti-tuberculosis drugs (ATD), making this disease very difficult to cure. This research uses secondary data from the Tanjung Pinang City Population Control and Family Planning Health Service for 2022-2023. The aim is to determine the relationship between compliance in taking Anti-Tuberculosis Drugs (ATD) and the results of acid-fast bacteria (AFB) examinations of TB patients in Tanjung Pinang City. The research methodology was observational analytic using a cross-sectional design, with a total sampling technique from pulmonary TB patients with positive AFB, negative AFB with positive thorax and extrapulmonary, 252 TB patients. Data analysis used the Fisher Exact test with a confidence level of 95%. The results of data analysis showed that 91.3% of patients complied in taking drugs, and 87.3% recovered with negative AFB results. Fisher Exact analysis showed a significant difference in proportion between compliance in taking anti-tuberculosis drugs and the results of AFB examination of pulmonary TB patients with a p-value of 0.000 (p &lt; ∝0.05). The conclusion from this study is that there is a relationship between compliance in taking anti-tuberculosis drugs and the results of AFB examinations of pulmonary TB patients in Tanjung Pinang City in 2022-2023. Keywords: Pulmonary TB, ATD, (AFB), Ziehl Neelsen

The Tuberculosis Drug Candidate SQ109 and Its Analogs Have Multistage Activity against Plasmodium falciparum.

Toward repositioning the antitubercular clinical candidate SQ109 as an antimalarial, analogs were investigated for structure-activity relationships for activity against asexual blood stages of the human malaria parasite Plasmodium falciparum pathogenic forms, as well as transmissible, sexual stage gametocytes. We show that equipotent activity (IC50) in the 100-300 nM range could be attained for both asexual and sexual stages, with the activity of most compounds retained against a multidrug-resistant strain. The multistage activity profile relies on high lipophilicity ascribed to the adamantane headgroup, and antiplasmodial activity is critically dependent on the diamine linker. Frontrunner compounds showed conserved activity against genetically diverse southern African clinical isolates. We additionally validated that this series could block transmission to mosquitoes, marking these compounds as novel chemotypes with multistage antiplasmodial activity.

Evaluating the efficacy of whole genome sequencing in predicting susceptibility profiles for first-line antituberculosis drugs

ObjectivesThis study aimed to examine the efficacy of whole genome sequencing (WGS) in accurately predicting susceptibility profiles, potentially eliminating the need for conventional phenotypic drug susceptibility testing (pDST) for first-line antituberculosis drugs in routine tuberculosis diagnosis. MethodsOver the period of 2017 to 2020, 1114 Mycobacterium tuberculosis complex isolates were collected with drug susceptibility testing conducted using the MGIT960 system and WGS performed for predicting drug resistance profiles. In addition, we implemented a new algorithm with an updated WGS workflow, omitting pan-susceptible strains from pDST. ResultsResults showed that out of 1075 analysed isolates, WGS-based genotypic sensitivity predictions for isoniazid, rifampicin, ethambutol, and pyrazinamide were 100% (95% CI, 99.6–100%), 100% (95% CI, 99.62–100%), 99.8% (95% CI, 99.26–99.94%), and 100% (95% CI, 99.63–100%), respectively. In contrast, the WGS-based genotypic resistance prediction, was 98.85% (95% CI, 93.77–99.79%) for isoniazid, 94.74% (95% CI, 82.71–98.54%) for rifampicin, 86.96% (95% CI, 67.87–95.46%) for ethambutol, and 75.7% (95% CI, 59.9–86.63%) for pyrazinamide. Moreover, WGS enabled the implementation of a new testing algorithm that made it unnecessary to perform pDST in 954 of all 1075 samples (88.7%) and in 890 of 901 pan-susceptible samples (98.8%). DiscussionIntegrating WGS into tuberculosis management offers significant potential to replace phenotypic drug susceptibility testing, especially for problematic drugs like pyrazinamide and ethambutol, potentially improving treatment outcomes.

Mycobacterial Targets for Thiourea Derivatives: Opportunities for Virtual Screening in Tuberculosis Drug Discovery.

Tuberculosis (TB) remains a primary global health concern, necessitating the discovery and development of new anti-TB drugs, mainly to combat drug-resistant strains. In this context, thiourea derivatives have emerged as promising candidates in TB drug discovery due to their diverse chemical structures and pharmacological properties. This review aimed to explore this potential, identifying and exploring molecular targets for thiourea derivatives in Mycobacterium tuberculosis (Mtb) and the potential application of virtual screening techniques in drug discovery. We have compiled a comprehensive list of possible molecular targets of thiourea derivatives in Mtb. The enzymes are primarily involved in the biosynthesis of various cell wall components, including mycolic acids, peptidoglycans, and arabinans, or targets in the branched-chain amino acid biosynthesis (BCAA) pathway and detoxification mechanisms. We discuss the potential of these targets as critical constituents for the design of novel anti-TB drugs. Besides, we highlight the opportunities that virtual screening methodologies present in identifying potential thiourea derivatives that can interact with these molecular targets. The presented findings contribute to the ongoing efforts in TB drug discovery and lay the foundation for further research in designing and developing more effective treatments against this devastating disease.