Mycobacterium tuberculosis (Mtb) must cope with exogenous oxidative stress imposed by the host. Unlike other antioxidant enzymes, Mtb’s thioredoxin reductase TrxB2 has been predicted to be essential not only to fight host defenses but also for in vitro growth. However, the specific physiological role of TrxB2 and its importance for…
Granulomas are the pathological hallmark of tuberculosis (TB). However, their function and mechanisms of formation remain poorly understood. To understand the role of granulomas in TB, we analyzed the proteomes of granulomas from subjects with tuberculosis in an unbiased manner. Using laser-capture microdissection, mass spectrometry and confocal microscopy, we generated…
Isoniazid (INH) remains one of the cornerstones of antitubercular chemotherapy for drug-sensitive strains of M. tuberculosis bacteria. However, the increasing prevalence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains containing mutations in the KatG enzyme, which is responsible for the activation of INH into its antitubercular form, have rendered this…
Pyrazinamide (PZA) is one of only two sterilizing drugs in the first-line antituberculosis regimen. Its activity is strongly pH dependent; the MIC changes by several orders of magnitude over a range of pH values that may be encountered in various in vivo compartments. We recently reported selective inactivity of PZA…
Adjunctive host-directed therapy is emerging as a new potential approach to improve the outcome of conventional antimicrobial treatment for tuberculosis (TB). We tested the ability of a phosphodiesterase-4 inhibitor (PDE4i) CC-11050, co-administered with the first-line anti-TB drug isoniazid (INH), to accelerate bacillary killing and reduce chronic inflammation in the lungs…
New regimens based on two or more novel agents are sought to shorten or simplify treatment of tuberculosis (TB). Pretomanid (PMD) is a nitroimidazole in phase 3 trials that has significant bactericidal activity alone and in combination with bedaquiline (BDQ) and/or pyrazinamide (PZA). We previously showed that the novel combination…
Moxifloxacin (MFX) and levofloxacin (LFX), class of fluoroquinolone antibiotics, are the two most prescribed drugs to multidrug resistant tuberculosis (MDR-TB) patients. A single, sensitive and reliable LC-ESI-MS/MS method was developed and validated to simultaneously quantitate the levels of these drugs in human serum where enrofloxacin (EFX) was used as internal…
Pretomanid (PA-824) is an important nitroimidazole antitubercular agent in late stage clinical trials. However, pretomanid is limited by poor solubility and high protein binding, which presents opportunities for improvement in its physiochemical properties. Conversely, the oxazolidinone linezolid has excellent physicochemical properties and has recently shown impressive activity for the treatment…
