Recent Advances in Antituberculous Drug Development and Novel Drug Targets

Haruaki Tomioka, PhD; Yutaka Tatano, PhD; Ko Yasumoto, PhD; Toshiaki Shimizu, PhD

Disclosures

Expert Rev Resp Med. 2008;2(4):455-471. 

In This Article

New Promising Drug Targets of MTB

It is logical to design compounds capable of interfering with specific bacterial targets involved in biosynthesis or cellular mechanisms of membrane permeability and transport, which are closely related to the manifestation of mycobacterial virulence in hosts. In this respect, critical information regarding the entire genome of MTB has recently been elucidated.[8,9] In conjunction with advancing knowledge on various mycobacterial virulence genes, this is progressing our efforts to identify genes that code for new potential drug targets. Employing such knowledge on the mycobacterial genome and virulence factors, drug design applying quantitative structure-activity relationship (QSAR) may play a central role in the development of anti-tuberculous drugs in the near future.[10] A number of bacterial virulence genes have been cloned for MTB and other mycobacteria, and their roles concerning the manifestation of mycobacterial pathogenicity in host animals have been examined.[11,12] At present, high-resolution structures of the gene products (usually mycobacterial enzymes) encoded by such virulence genes are available, and structure-based inhibitor design is now underway, with the prospect of generating new classes of drugs that are potently active against mycobacteria, particularly persistent and dormant types of MTB organisms.[2,3,11,13,14] Such structural bioinformatics-based approaches offer a promising strategy to identify new classes of anti-tuberculous drugs.

However, the following problems should be noted. First, many studies have revealed that the high-throughput screening (HTS) of a library of organic compounds against MTB based on appropriate drug targets is not as easy as initially expected, because of, for example, the low binding affinity and electron charge of test molecules and difficulty in measuring the activity against whole mycobacterial cells. Second, bioinformatics approaches are difficult to apply to TB, since, at present, our knowledge of intracellular signal-transduction and metabolic pathways of MTB organisms is still limited. Thus, furthermore, marked efforts to comprehensively elucidate the precise roles and functions of mycobacterial gene products in intracellular pathways of MTB organisms are necessary to validate the structural bioinformatics-based approaches for the screening, identification and chemical design of novel anti-TB drugs. In this context, as an idealistic argument, it is necessary to logically depict the sequence of biochemical metabolic events associated with target proteins (enzymes) and genes. However, at present, many studies are generally undertaken by selectively focusing on one or a few target proteins. Thus, postgenome studies on the detailed biological and biochemical characteristics of whole gene products of MTB are urgently required. The major studies that have been carried out based on the new drug targets of MTB organisms are described later. The new promising drug targets and their properties are indicated in Table 1 . These drug targets are particularly interesting, since they are closely related to the virulence of MTB pathogens.

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