Long-acting injectable (LAI) drug formulations represent a transformative modality in modern therapeutics, delivering medications that maintain therapeutic effects over extended periods. While initially developed to improve patient adherence and acceptability for applications such as hormonal contraception and chronic conditions, including psychiatric disorders, their recent success in HIV treatment and prevention…
Mycobacterium tuberculosis (Mtb) is responsible for more deaths per year than any other infectious disease. Resistance of circulating Mtb to the standard of care treatment regimen is an urgent global health crisis for which novel antibiotic treatments are needed. We have developed extremely potent, orally bioavailable, small-molecule inhibitors of inosine…
Young children with exposure to or infection with are at high risk of developing tuberculosis disease, and postexposure tuberculosis preventive treatment decreases this risk. Evidence is limited regarding the dosing and safety of the 12-dose once-weekly rifapentine and isoniazid regimen (3HP) for tuberculosis preventive treatment in children younger than 2…
Acyldepsipeptides (ADEPs) are potent ClpP dysregulators that are active against a range of Gram-positive bacteria, but have limited potency against Mycobacterium tuberculosis (Mtb). To address potency, we employed a strategy of macrocycle rigidification and side-chain optimization enabled by a novel solid-phase peptide synthesis route. Among 35 compounds synthesized, ADEP 19…
The GID/CTLH E3 ligase complex is implicated in several biological processes, yet its full substrate repertoire remains poorly defined. We recently identified the complex as a broad modulator of macrophage responses to Mycobacterium tuberculosis (Mtb) infection. Here, we use label-free proteomics and diGly capture analysis of Mtb-infected macrophages to define…
Preclinical tuberculosis (TB) drug evaluation relies heavily on mouse infection models. Drug efficacy varies depending on inoculum and the timing of treatment initiation. These differences reflect, in part, physiological adaptations of () to host immune pressure. We used novel molecular markers of pathogen health (RS ratio and SEARCH-TB) to contrast…
The epidemiology of tuberculosis in Taiwan has been influenced by the introduction of multiple Mycobacterium tuberculosis lineages and by the ageing of the population. We conducted a population-based study to investigate M tuberculosis transmission in Kaohsiung, a city in southern Taiwan.
Treatment optimization through pharmacokinetic evaluation is needed to improve outcomes in tuberculous meningitis (TBM). Clinical assessment of drug penetration into the central nervous system (CNS) is limited to cerebrospinal fluid (CSF) sampling, which may not reflect drug exposures at the site-of-disease. We characterized the pharmacokinetics of antituberculosis drugs in CNS…
