Tuberculosis is a global public health problem with emergence of multidrug-resistant infections. Previous epidemiological studies of tuberculosis in Thailand have identified a clonal outbreak multidrug-resistant strain of Mycobacterium tuberculosis in the Kanchanaburi province, designated “MKR superspreader”, and this particular strain later was found to also spread to other regions. In…
Interrupting transmission is an attractive anti-tuberculosis (TB) strategy but it remains underexplored owing to our poor understanding of the events surrounding transfer of Mycobacterium tuberculosis (Mtb) between hosts. Determining when live, infectious Mtb bacilli are released and by whom has proven especially challenging. Consequently, transmission chains are inferred only retrospectively,…
Macrophages help defend the host against Mycobacterium tuberculosis (Mtb), the major cause of tuberculosis (TB). Once phagocytized, Mtb resists killing by macrophages, replicates inside them, and leads to their death, releasing Mtb that can infect other cells. We found that the death of Mtb-infected mouse macrophages in vitro does not…
The approval of bedaquiline has placed energy metabolism in the limelight as an attractive target space for tuberculosis antibiotic development. While bedaquiline inhibits the mycobacterial F F ATP synthase, small molecules targeting other components of the oxidative phosphorylation pathway have been identified. Of particular interest is Telacebec (Q203), a phase…
Mycobacterium tuberculosis (Mtb) remains the deadliest pathogenic bacteria worldwide. The search for new antibiotics to treat drug-sensitive as well as drug-resistant tuberculosis has become a priority. The essential enzyme phenylalanyl-tRNA synthetase (PheRS) is an antibacterial drug target because of the large differences between bacterial and human PheRS counterparts. In a…
Tuberculosis (TB) kills more people than any other infectious disease. Challenges for developing better treatments include the complex pathology due to within-host immune dynamics, interpatient variability in disease severity and drug pharmacokinetics-pharmacodynamics (PK-PD), and the growing emergence of resistance. Model-informed drug development using quantitative and translational pharmacology has become increasingly…
Hollow fiber systems (HFSs) have been widely applied to study pharmacokinetic-pharmacodynamic (PK-PD) relationships in antibiotic research and development. The system comprises a bundle of high-density hollow capillary fibers that conduct a flow of medium with or without drug and an extra-capillary space (ECS) inoculated with the pathogen of interest. The…
Treatment of tuberculosis necessitates combination therapy. Therefore, development of new tuberculosis therapies should consider multidrug effects because specific combinations may improve or reduce treatment efficacy through synergistic or antagonistic drug interactions, respectively. The standard assay of drug interactions is a checkerboard assay, wherein the drug-dose combinations are well-sampled across broad…
