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Chapter 32 : Strategies for New Drug Development
This chapter focuses on the prospects for using a fundamental molecular approach to identification of novel lead compounds for new drug development. A section reviews existing and potential drug targets in Mycobacterium tuberculosis. The chapter then discusses distinctive features of mycobacteria relevant to drug design, and considers experimental approaches applicable to rational drug discovery programs. Most antibacterial agents inhibit biosynthetic pathways involved in the production of macromolecules. Streptomycin, the first antibiotic available for widespread use in treatment of tuberculosis, is a member of the aminoglycoside family that disrupts bacterial protein synthesis. An important strategy for enhancing the activity of sulfonamides against some bacteria has been their use in combination with trimethoprim, a drug that inhibits a subsequent step in the tetrahydrofolate pathway catalyzed by the enzyme dihydrofolate reductase. Rifampin is a key drug in mycobacterial therapy that has a broad antibacterial spectrum and a well-defined target. Ethambutol has a polyamine-like structure and was originally thought to interfere with RNA synthesis. M. tuberculosis isolates with defects in the katG gene encoding a catalase-peroxidase enzyme develop resistance to isoniazid (INH), indicating a possible role for the enzyme in intracellular activation of the drug. The recent development of molecular genetic systems for mycobacteria opens a range of novel opportunities for drug discovery.