Drug metabolism is generally associated with liver enzymes. However, in the case of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), Mtb-mediated drug metabolism plays a significant role in treatment outcomes. Mtb is equipped with enzymes that catalyse biotransformation reactions on xenobiotics with consequences either in its favour or…
Spectinamides are a novel series of spectinomycin analogs being developed for the treatment of tuberculosis. The preclinical lead spectinamide 1599 is an antituberculosis drug that possesses robust in vivo efficacy, good pharmacokinetic properties, and excellent safety profiles in rodents. In individuals infected with Mycobacterium tuberculosis or Mycobacterium bovis, causative agents…
Mycobacterium tuberculosis (Mtb), perhaps more than any other organism, is intrinsically appealing to chemical biologists. Not only does the cell envelope feature one of the most complex heteropolymers found in nature but many of the interactions between Mtb and its primary host (we humans) rely on lipid and not protein…
Caseous necrosis is a hallmark of tuberculosis (TB) pathology and creates a niche for drug-tolerant persisters within the host. Cavitary TB and high bacterial burden in caseum require longer treatment duration. An model that recapitulates the major features of Mycobacterium tuberculosis (Mtb) in caseum would accelerate the identification of compounds…
Antituberculosis therapy (ATT) causes a rapid and distinct alteration in the composition of the intestinal microbiota that is long lasting in both mice and humans. This observation raised the question of whether such antibiotic-induced changes in the microbiome might affect the absorption or gut metabolism of the tuberculosis (TB) drugs…
A regimen comprised of bedaquiline (BDQ, or B), pretomanid, and linezolid (BPaL) is the first oral 6-month regimen approved by the U.S. Food and Drug Administration and recommended by the World Health Organization for the treatment of extensively drug-resistant tuberculosis. We used a well-established BALB/c mouse model of tuberculosis to…
New oxazolidinones are in clinical development for the treatment of tuberculosis and nontuberculous mycobacterial (NTM) infections, as a replacement for linezolid and tedizolid, which cause mitochondrial toxicity after prolonged treatment. Here, we carried out side-by-side measurements of mitochondrial protein synthesis inhibition and activity against clinically relevant mycobacterial pathogens of approved…
