Lysine ɛ-aminotransferase (LAT) is a protein involved in lysine catabolism, and it plays a significant role during the persistent/latent phase of Mycobacterium tuberculosis (MTB), as observed by its up-regulation by ~40-fold during this stage. We have used the crystal structure of MTB LAT in external aldimine form in complex with its substrate lysine as a template to design and identify seven lead compounds with IC50 ranging from 18.06 to > 90 μm. We have synthesized 21 compounds based on the identified lead, and compound 21 [2,2'-oxybis(N'-(4-fluorobenzylidene)acetohydrazide)] was found to be the most active with MTB LAT IC50 of 0.81 ± 0.03 μm. Compound 21 also showed a 2.3 log reduction in the nutrient-starved MTB model and was more potent than standard isoniazid and rifampicin at the same dose level of 10 μg/mL.
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http://dx.doi.org/10.1111/cbdd.12655 | DOI Listing |
Clin Pharmacokinet
January 2025
Facultés de Médecine et de Pharmacie de Lyon, Univ Lyon, Université Claude Bernard Lyon 1, Lyon, France.
Background And Objective: Limited information is available on the pharmacokinetics of rifampicin (RIF) along with that of its active metabolite, 25-deacetylrifampicin (25-dRIF). This study aimed to analyse the pharmacokinetic data of RIF and 25-dRIF collected in adult patients treated for tuberculosis.
Methods: In adult patients receiving 10 mg/kg of RIF as part of a standard regimen for drug-susceptible pulmonary tuberculosis enrolled in the Opti-4TB study, plasma RIF and 25-dRIF concentrations were measured at various occasions.
Autoimmun Rev
January 2025
Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India. Electronic address:
Tuberculosis (TB), caused by Mycobacterium TB, is the most significant infectious cause of mortality across the globe. While TB disease can prey on immunocompetent individuals, it is more likely to occur in immunocompromised individuals. Immune-mediated inflammatory diseases (IMIDs) are a group of diseases (rheumatoid arthritis, inflammatory bowel disease, ankylosing spondylitis, psoriasis, hidradenitis suppurative, autoimmune blistering diseases, and others) where there may be a need for systemic immunosuppression to control the disease manifestations, treat symptoms and improve long term outcomes.
View Article and Find Full Text PDFSemin Respir Crit Care Med
January 2025
Monoclonal Antibody Discovery (MAD) Lab, Fondazione Toscana Life Sciences, Siena, Italy.
In this review, we present the efforts made so far in developing effective solutions to prevent infections caused by seven major respiratory pathogens: influenza virus, respiratory syncytial virus (RSV), the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), , (), , and . Advancements driven by the recent coronavirus disease 2019 (COVID-19) crisis have largely focused on viruses, but effective prophylactic solutions for bacterial pathogens are also needed, especially in light of the antimicrobial resistance (AMR) phenomenon. Here, we discuss various innovative key technologies that can help address this critical need, such as (a) the development of Lung-on-Chip ex vivo models to gain a better understanding of the pathogenesis process and the host-microbe interactions; (b) a more thorough investigation of the mechanisms behind mucosal immunity as the first line of defense against pathogens; (c) the identification of correlates of protection (CoPs) which, in conjunction with the Reverse Vaccinology 2.
View Article and Find Full Text PDFThe mycomembrane of mycobacteria has long been regarded as the primary barrier to the accumulation of molecules within these bacteria. Understanding accumulation beyond the mycomembrane of ( ) is crucial for developing effective antimycobacterial agents. This study investigates two design principles commonly found in natural products and mammalian cell-permeable peptides - backbone -methylation and macrocyclization - aimed at enhancing accumulation.
View Article and Find Full Text PDFBacterial serine-threonine protein kinases (STKs) regulate diverse cellular processes associated with cell growth, virulence, and pathogenicity. They are evolutionarily related to the druggable eukaryotic STKs. However, an incomplete knowledge of how bacterial STKs differ from their eukaryotic counterparts and how they have diverged to regulate diverse bacterial signaling functions presents a bottleneck in targeting them for drug discovery efforts.
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