New approaches to tuberculosis--novel drugs based on drug targets related to toll-like receptors in macrophages.
Tuberculosis (TB) is one of the most important health concerns in the world, causing serious levels of morbidity and mortality, particularly in many developing countries. Unfortunately, the development of new anti-TB drugs with superior chemotherapeutic and prophylactic activity has been very slow. Thus, it is urgently necessary to develop novel kinds of antituberculosis drugs that exert their anti-Mycobacterium tuberculosis (MTB) activity through unique drug targets expressed by MTB organisms. At present, the drug targets of most current anti-TB drugs are primarily bacterial metabolic reactions and cell components that are indispensable to the growth and survival of MTB organisms in extracellular milieus, particularly in culture media. To develop novel and unique anti-TB drugs in the future, it is desirable to highlight the drug targets related to the bacterial ability to survive and replicate in host macrophages by escaping from a macrophage's bacterial killing mechanism during infection inside such phagocytes. For this purpose, it is reasonable to focus our research efforts on mycobacterial virulence factors that cross-talk and interfere with signaling pathways of host macrophages, because such virulence factors will provide intracellular milieus favorable to intramacrophage survival and growth of MTB. In this chapter, based on such a viewpoint and strategy, the present status of worldwide research on novel potential drug targets related to Toll-like receptor in the MTB pathogen will be described.
Department of Microbiology and Immunology, Shimane University School of Medicine, Izumo, Shimane 693-8501, Japan. tomioka@med.shimane-u.ac.jp.
Haruaki
H
Tomioka
D000942:Antigens, Bacterial / Q000235:genetics / Q000378:metabolism; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods*; D054884:Host-Pathogen Interactions / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate; D018664:Interleukin-12 / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D058990:Molecular Targeted Therapy; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D021281:Quantitative Structure-Activity Relationship; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D051193:Toll-Like Receptors / Q000378:metabolism*; D014376:Tuberculosis / Q000188:drug therapy / Q000276:immunology / Q000382:microbiology; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism
D000942:Antigens, Bacterial; D000995:Antitubercular Agents; D001426:Bacterial Proteins; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D051193:Toll-Like Receptors; D037521:Virulence Factors; D018664:Interleukin-12