3. Producción

Browse

Settings

Has files: NoSubject: search.filters.subject.Mycobacterium tuberculosis

Search Results

Now showing 1 - 3 of 3
  • Loading...
    Thumbnail Image
    Some of the metrics are blocked by your 
    consent settings
    Item type:Publication,
    Mycobacterium tuberculosis ribosomal protein S1 (RpsA) and variants with truncated C-terminal end show absence of interaction with pyrazinoic acid
    (Nature Research, 2020-12-01)
    Pyrazinamide (PZA) is an antibiotic used in first- and second-line tuberculosis treatment regimens. Approximately 50% of multidrug-resistant tuberculosis and over 90% of extensively drug-resistant tuberculosis strains are also PZA resistant. Despite the key role played by PZA, its mechanisms of action are not yet fully understood. It has been postulated that pyrazinoic acid (POA), the hydrolyzed product of PZA, could inhibit trans-translation by binding to Ribosomal protein S1 (RpsA) and competing with tmRNA, the natural cofactor of RpsA. Subsequent data, however, indicate that these early findings resulted from experimental artifact. Hence, in this study we assess the capacity of POA to compete with tmRNA for RpsA. We evaluated RpsA wild type (WT), RpsA ∆A438, and RpsA ∆A438 variants with truncations towards the carboxy terminal end. Interactions were measured using Nuclear Magnetic Resonance spectroscopy (NMR), Isothermal Titration Calorimetry (ITC), Microscale Thermophoresis (MST), and Electrophoretic Mobility Shift Assay (EMSA). We found no measurable binding between POA and RpsA (WT or variants). This suggests that RpsA may not be involved in the mechanism of action of PZA in Mycobacterium tuberculosis, as previously thought. Interactions observed between tmRNA and RpsA WT, RpsA ∆A438, and each of the truncated variants of RpsA ∆A438, are reported.
  • Loading...
    Thumbnail Image
    Some of the metrics are blocked by your 
    consent settings
    Item type:Publication,
    Quantitative 1H Nuclear Magnetic Resonance Assay for the Rapid Detection of Pyrazinamide Resistance in Mycobacterium tuberculosis from Sputum Samples
    (American Society for Microbiology, 2023-05-01)
    Tuberculosis (TB), caused by Mycobacterium tuberculosis, is one of the 10 leading killer diseases in the world. At least one-quarter of the population has been infected, and there are 1.3 million deaths annually. The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains challenges TB treatments. One of the drugs widely used in first- and second-line regimens is pyrazinamide (PZA). Statistically, 50% of MDR and 90% of XDR clinical strains are resistant to PZA, and recent studies have shown that its use in patients with PZA-resistant strains is associated with higher mortality rates. Therefore, the is an urgent need for the development of an accurate and efficient PZA susceptibility assay. PZA crosses the M. tuberculosis membrane and is hydrolyzed to its active form, pyrazinoic acid (POA), by a nicotinamidase encoded by the pncA gene. Up to 99% of clinical PZA-resistant strains have mutations in this gene, suggesting that this is the most likely mechanism of resistance. However, not all pncA mutations confer PZA resistance, only the ones that lead to limited POA production. Therefore, susceptibility to PZA may be addressed simply by its ability to form, or not, POA. Here, we present a nuclear magnetic resonance method to accurately quantify POA directly in the supernatant of sputum cultures collected from TB patients. The ability of the clinical sputum culture to hydrolyze PZA was determined, and the results were correlated with the results of other biochemical and molecular PZA drug susceptibility assays. The excellent sensitivity and specificity values attained suggest that this method could become the new gold standard for the determination of PZA susceptibility.
  • Loading...
    Thumbnail Image
    Some of the metrics are blocked by your 
    consent settings
    Item type:Publication,
    Half-sandwich ruthenium (II) complexes with N,O-Quinoxaline ligand: Synthesis, in silico affinity and Mycobacterium tuberculosis susceptibility
    (Elsevier BV, 2026-02-01)
    Tuberculosis (TB) remains one of the deadliest bacterial infections, despite the approval of new anti-bacterial drugs over the past decade. This persistent challenge is attributed to the emergence of drug-resistant Mycobacterium tuberculosis strains, which emphasizes the ongoing need for novel therapeutic options. In this research, the synthesis and characterization of novel half-sandwich ruthenium (II) complexes featuring a quinoxaline-based ligand (L), 3-(4-bromophenyl)quinoxaline-2-carboxylic acid, are reported. The three complexes [Ru(p-cymene)(I)(L)] (1),[Ru(p-cymene)(Cl)(L)] (2) and [Ru(benzene)(Cl)(L)] (3) were characterized by FTIR, NMR and HRMS. Additionally, the solid-state structures of1and2were determined by XRD, revealing geometries similar to a three-legged piano stool, with the Ru atom coordinated to the carboxylate oxygen and the quinoxaline nitrogen atoms of the ligand. Interaction with mycobacterial drug targets was explored and binding energies based on docking scores were estimated to assess their potential antituberculous activity. Strong interactions were observed between1and2and the targets Emb complex and ATP synthase, suggesting potential antituberculous activity. Furthermore, the susceptibility of M. tuberculosis H37Rv strain to these compounds was evaluated by determining their minimum inhibitory concentrations (MICs). Compounds2and3each displayed MIC values of 50 μg/mL, whereas compound1exhibited a MIC of 100 μg/mL, which falls within the range observed for first-line drugs such as pyrazinamide. These findings confirm their activity against M. tuberculosis.
      1