In Tuberculosis Trials Consortium Study 35, which investigated the optimal dosing and safety of once-weekly isoniazid and rifapentine (3HP) in 69 children requiring tuberculosis preventive therapy, 7 children with HIV received 50 mg of once-daily dolutegravir. Plasma dolutegravir concentrations were consistent with those predicted in children on dolutegravir not receiving…
Early bactericidal activity and time to sputum conversion are well-established study end points in both preclinical animal models and clinical trials for testing drug regimens for pulmonary tuberculosis (TB). The development and optimization of treatment-shortening drug regimens for TB have been challenged by disparities between these study end points and…
Eradication of tuberculosis requires new drugs targeting novel pathways. Although purine metabolism represents an essential antitubercular target, concerns about host nucleobase rescue limited its exploration. New data demonstrate that nucleobase levels in human lung tissue are insufficient to confer rescue, renewing interest in this pathway for tuberculosis drug discovery.
Since the release of the first Mycobacterium tuberculosis genome in 1998, major advances have been made in understanding the biology of this pathogen, the leading infectious cause of death in modern human history. In this Review, we outline the physiological and metabolic features thought to underpin the survival, evasion and…
Multiple studies have reported genes in the M. tuberculosis (Mtb) genome that are under diversifying selection, based on genetic variants among Mtb clinical isolates. These might reflect adaptions to selection pressures associated with modern clinical treatment of TB. Many, but not all, of these genes under selection are related to…
Understanding the functional impact of bacterial genetic diversity is crucial for linking pathogen variants to clinical outcomes. Here, we introduce a high-throughput cytological profiling pipeline optimized for (Mtb) clinical strains, integrating OD-calibrated feature analysis and high-content microscopy. Our system quantifies single-bacterium morphological and physiological traits related to DNA replication, redox…
A key challenge in preclinical tuberculosis drug development is identifying optimal antibiotic combinations. Drug interactions are complex because one drug may affect () physiology in a way that alters the activity of another drug. Conventional pharmacodynamic evaluation based on colony-forming units (CFU) does not provide information about this physiologic interaction…
Preclinical and clinical study data show that combining bedaquiline (B or BDQ), moxifloxacin (M), and pyrazinamide (Z), known as BMZ, has potent antimicrobial activity that might shorten treatment duration for drug-susceptible pulmonary tuberculosis.
