第77回総会特別講演 : 新しい抗結核薬開発の展望

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Tuberculosis (TB) is a growing international health concern, since it is the leading infectious cause of death in the world today. Moreover, the resurgence of TB in indus-trialized countries and the worldwide increase in the preva-lence of Mycobacterium avium complex (MAC) infections in immunocompromised hosts have prompted the quest for new antimycobacterial drugs. In particular, the appearance of multidrug-resistant (MDR) strains of M tuberculosis, which exhibit in vitro resistance to at least two major antituberculous drug (usually INH and RFP) and cause intractable TB, has greatly contributed to the increased incidence of TB. Because of the global health problems of TB, the increasing rate of MDR-TB and the high rate of a co-infection with HIV, the development of potent new antituberculous drugs without cross-resistance with known antimycobacterial agents is urgently needed. In this article, I reviewed the following areas. First, I briefly reviewed some new findings (mainly reported after 2000) on the pharmacological status of rifamycin derivatives (rifabutin, rifapentine, and rifalazil), fluoroquinolones (cipro-floxacin, ofloxacin, sparfloxacin, levofloxacin, gatifloxacin, sitafloxacin, moxifloxacin, and others), and new macrolides (clarithromycin, azithromycin, and roxithromycin). Second, I decribed other types of agents which are being developed as antimycobacterial drugs. Some of the agents discussed are already under preliminary clinical investigation, and others appear to be promising candidates for future devel-opment. In this review, the status of the development of new antimycobacterial, especially antituberculous agents including oxazolidinone (PNU-100480), 5-nitroimidazole (CGI 17341), 2-pyridone (ABT-255), new riminophenazines, nitroimi-dazopyran (PA-824), new ketolides (ABT-773, telithromycin) and defensins (human neutrophil peptide-1), was examined. Third, the development of new antitubercular drugs was discussed according to the potential pharmacological target. New critical information on the whole genome of M tuberculosis recently elucidated and increasing knowledge on various mycobacterial virulence genes will promote the progression in the identification of genes that code for new drug targets. Using such findings on mycobacterial genomes, drug devel-opment using quantitative structure-activity relationship may be possible in the near future. In this review, I described the screening of drugs that have an inhibitory activity against dTDP-rhamnose synthesis of M tuberculosis, as a new drug target of the organism. In addition, I discussed the usefulness of antisense oligo DNAs specific to mycobacterial genes encoding certain metabolic enzymes or virulence factors that play roles in the bacterial escape from antimicrobial mechanisms of host macrophages. Fourth, I reviewed the drug vehicles which enable effica-cious drug delivery to their target in vivo. The usefulness of poly (DL-lactide-co-glycolide) microsphere technology, which enables the encapsulated drugs to deliver the requested doses of them for prolonged time periods by a single shot without causing any toxicity and, moreover, enables the highly targeted delivery of the drugs to host macrophages, was discussed.
2002-08-15

第77回総会特別講演 : 新しい抗結核薬開発の展望

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