linezolid and Tuberculosis--Multidrug-Resistant

Despite enormous efforts have been made in the hunt for new drugs, tuberculosis (TB) still remains the first bacterial cause of mortality worldwide, causing an estimated 8.6 million new cases and 1.3 million deaths in 2012. Multi-drug resistant-TB strains no longer respond to first-line drugs and are inexorably spreading with an estimated 650,000 cases as well as extensively-drug resistant-TB strains, which are resistant to any fluoroquinolone and at least one of the second-line drugs, with 60,000 cases. Thus the discovery and development of new medicines is a major keystone for tuberculosis treatment and control. After decades of dormancy in the field of TB drug development, recent efforts from various groups have generated a promising TB drug pipeline. Several new therapeutic agents are concurrently studied in clinical trials together with much activity in the hittolead and lead optimization stages. In this article we will review the recent advances in TB drug discovery with a special focus on structure activity relationship studies of the most advanced compound classes.

Topics: Animals; Antitubercular Agents; Humans; Mycobacterium tuberculosis; Structure-Activity Relationship; Tuberculosis; Tuberculosis, Multidrug-Resistant

Tuberculosis (TB) is one of the world's most deadly infectious diseases resulting in nearly 1.3 million deaths annually and infecting nearly one-quarter of the population. para-Aminosalicylic acid (PAS), an important second-line agent for treating drug-resistant Mycobacterium tuberculosis, has moderate bioavailability and rapid clearance that necessitate high daily doses of up to 12 g per day, which in turn causes severe gastrointestinal disturbances presumably by disruption of gut microbiota and host epithelial cells. We first synthesized a series of alkyl, acyloxy and alkyloxycarbonyloxyalkyl ester prodrugs to increase the oral bioavailability and thereby prevent intestinal accumulation as well as undesirable bioactivation by the gut microbiome to non-natural folate species that exhibit cytotoxicity. The pivoxyl prodrug of PAS was superior to all of the prodrugs examined and showed nearly quantitative absorption. While the conceptually simple prodrug approach improved the oral bioavailability of PAS, it did not address the intrinsic rapid clearance of PAS mediated by N-acetyltransferase-1 (NAT-1). Thus, we next modified the PAS scaffold to reduce NAT-1 catalyzed inactivation by introduction of groups to sterically block N-acetylation and fluorination of the aryl ring of PAS to attenuate N-acetylation by electronically deactivating the para-amino group. Among the mono-fluorinated analogs prepared, 5-fluoro-PAS, exhibited the best activity and an 11-fold decreased rate of inactivation by NAT-1 that translated to a 5-fold improved exposure as measured by area-under-the-curve (AUC) following oral dosing to CD-1 mice. The pivoxyl prodrug and fluorination at the 5-position of PAS address the primary limitations of PAS and have the potential to revitalize this second-line TB drug.

Topics: Aminosalicylic Acid; Animals; Antitubercular Agents; Biological Availability; Mice; Prodrugs; Tuberculosis; Tuberculosis, Multidrug-Resistant

Tuberculosis (TB) remains a serious public health challenge, and the research and development of new anti-TB drugs is an essential component of the global strategy to eradicate TB. In this work, we discovered a conformationally constrained oxazolidinone

Topics: Animals; Chlorocebus aethiops; Drug Design; Female; Hep G2 Cells; Humans; Mice; Microbial Sensitivity Tests; Molecular Conformation; Mycobacterium tuberculosis; Oxazolidinones; Safety; Tuberculosis, Multidrug-Resistant; Vero Cells

Significant increases in the MIC(90)s of linezolid in multidrug-resistant Mycobacterium tuberculosis isolates were seen between the baseline period of 2001 to 2003 (0.5 microg/ml) and 2004 (2 microg/ml). The MICs were 4 microg/ml in three strains. Both fluoroquinolones (except levofloxacin) and kanamycin were found to have statistically significant degrees of concordance with linezolid.

Topics: Acetamides; Antitubercular Agents; Drug Resistance, Bacterial; Fluoroquinolones; Humans; Linezolid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Oxazolidinones; Taiwan; Tuberculosis; Tuberculosis, Multidrug-Resistant