To identify new compounds that can effectively inhibit Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), we screened, synthesized, and evaluated a series of novel aryl fluorosulfate derivatives for their in vitro inhibitory activity against Mtb. Compound 21b exhibited an in vitro minimum inhibitory concentration (MIC) of 0.06 µM against…
A major reason that curing tuberculosis requires prolonged treatment is that drug exposure changes bacterial phenotypes. The physiologic adaptations of that survive drug exposure have been obscure due to low sensitivity of existing methods in drug-treated animals. Using the novel SEARCH-TB RNA-seq platform, we elucidated phenotypes in mice treated for…
Tuberculosis meningitis (TBM) is essentially treated with the first-line regimen used against pulmonary tuberculosis, with a prolonged continuation phase. However, clinical outcomes are poor in comparison, for reasons that are only partially understood, highlighting the need for improved preclinical tools to measure drug distribution and activity at the site of…
Contezolid is a new oxazolidinone with and activity against comparable to that of linezolid. Pre-clinical and clinical safety studies suggest it may be less toxic than linezolid, making contezolid a potential candidate to replace linezolid in the treatment of drug-resistant tuberculosis. We evaluated the dose-ranging activity of contezolid, alone and…
BTZ-043, a suicide inhibitor of the cell wall synthesis decaprenylphosphoryl-beta-D-ribose 2′ epimerase, is under clinical development as a potential new anti-tuberculosis agent. BTZ-043 is potent and bactericidal but has limited activity against non-growing bacilli in rabbit caseum. To better understand its behavior , BTZ-043 was evaluated for efficacy and spatial…
The World Health Organization has developed target product profiles containing minimum and optimum targets for key characteristics for tests for tuberculosis treatment monitoring and optimization. Tuberculosis treatment optimization refers to initiating or switching to an effective tuberculosis treatment regimen that results in a high likelihood of a good treatment outcome.
New drugs to treat tuberculosis which target intractable bacterial populations are required to develop shorter and more effective treatment regimens. The benzene amide ether scaffold has activity against intracellular , but low activity against extracellular, actively replicating . We determined that these molecules have bactericidal activity against non-replicating but not…
Studying treatment duration for rifampicin-resistant and multidrug-resistant tuberculosis (MDR/RR-TB) using observational data is methodologically challenging. We aim to present a hypothesis generating approach to identify factors associated with shorter duration of treatment.
