Screening for novel antituberculosis agents that are effective against multidrug resistant tuberculosis.
The challenges in preventing and controlling tuberculosis are further complicated by the deadly rise of multi-drug-resistant tuberculosis (MDR-TB). Recognizing the seriousness of the situation, we initiated a program to screen new agents that would satisfy these unmet needs and have a favorable safety profile. Mycobacteria are well known for their lipid-rich properties. In Mycobacterium tuberculosis, mycolic acid in particular has been established the wall component related to the pathogenesis in the host. There are approximately 250 identified genes related to biosynthesis of the lipid turnover that contain InhA, the main target of isoniazid. Thus, the logical approach for developing a chemotherapy agent against tubercle bacilli included screening compounds that could inhibit the biosyntheses of mycolic acid and that had a novel chemical structure to ensure improved efficacy against MDR-TB. Some of the screening systems established for those purposes and some of the candidates are outlined.
Matsumoto
Makoto
M
Microbiological Research Institute, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan. m_matsumoto@research.otsuka.co.jp
Hashizume
Hiroyuki
H
Tsubouchi
Hidetsugu
H
Sasaki
Hirofumi
H
Itotani
Motohiro
M
Kuroda
Hideaki
H
Tomishige
Tatsuo
T
Kawasaki
Masanori
M
Komatsu
Makoto
M
D000995:Antitubercular Agents / Q000494:pharmacology*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D018432:Drug Resistance, Multiple; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology / Q000627:therapeutic use; D008055:Lipids; D009171:Mycolic Acids / Q000037:antagonists & inhibitors; D014376:Tuberculosis / Q000188:drug therapy*
D000995:Antitubercular Agents; D008055:Lipids; D009171:Mycolic Acids; D007538:Isoniazid