title: TB drug discovery: addressing issues of persistence and resistance.
abstract: Tuberculosis remains a leading cause of mortality worldwide into the 21st century. Among the main obstacles to the global control of the disease are emerging multi-drug resistant strains and the recalcitrance of persistent infections to treatment with conventional anti-TB drugs. Here we review recent developments in our understanding of some of the pathways involved in a persistent infection and pathogenesis of Mycobacterium tuberculosis, which reveal new targets for drug development. We describe the high-resolution crystal structures of enzymes of the glyoxylate shunt, isocitrate lyase and malate synthase, and of the cyclopropane synthases of mycolic acid biosynthesis. Structure-based drug design is now underway with the potential to lead to the development of new anti-tuberculars effective against persistent and resistant Mycobacterium tuberculosis infections.
authors.affiliation: Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843-2128, USA.
authors.forename: Clare V
authors.initials: CV
authors.lastname: Smith
authors.forename: Vivek
authors.initials: V
authors.lastname: Sharma
authors.forename: James C
authors.initials: JC
authors.lastname: Sacchettini
mesh_terms: D000595:Amino Acid Sequence; D000995:Antitubercular Agents / Q000627:therapeutic use*; D015195:Drug Design; D006801:Humans; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics*; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents